Novel quinoxalinone derivatives

ABSTRACT

A quinoxalinone derivative of the formula (I):  
                 
or a pharmaceutically acceptable salt or ester thereof, wherein; X is NH, S or the like; Y is O or the like; 
 
the partial structure  
                 
 
is, for example, the formula:  
                 
         B 1 , B 2 , . . . , B n-1  and B n , (in which n is 4, 5 or 6) are each independently CH, N or the like;    B′ 1 , B′ 2 , . . . , B′ n-1  and B′ n  (in which n is 4, 5 or 6) are each independently hydrogen or the like; and R is hydrogen, lower alkyl or the like.

TECHNICAL FIELD

The present invention relates to a novel quinoxalinone derivative whichis useful as pharmaceuticals, a process for preparing the same and acomposition containing the same as an active ingredient.

BACKGROUND ART

In the process of normal cell proliferation, cell division and its pauseoccur orderly in accordance with cell cycle, while cancer cellproliferation is characterized by disorder. For this reason, abnormalityin the cell cycle control mechanism is supposed to have a directrelation with oncogenesis or malignant alteration of cancer. The cellcycle of a mammalian cell is regulated by a serine/threonine kinasecalled cyclin-dependent kinase (hereinafter abbreviated as Cdk) family,and Cdk needs to form a complex with the regulatory subunit calledcyclin in order to exhibit its enzymatic activity. A cyclin itself alsohave a family, and each Cdk molecule is considered to regulate theprogression of a certain cell cycle by forming a complex with a cyclinmolecule which is expressed specifically at the corresponding stage ofthe cell cycle. For example, D type cyclin, in combination with Cdk4 orCdk6, regulates the progression of G1 phase, cyclin E-Cdk2 regulatesG1/S boundary, cyclin A-Cdk2 regulates the progression of S phase, andcyclin B-cdc2 regulates the progression of G2/M, respectively. Inaddition, three sub-types D1, D2 and D3 are known as a D type cyclin,and moreover the activity of Cdk is considered to be regulated not onlyby its association with cyclins but also byphosphorylation/dephosphorylation of Cdk molecules, degradation ofcyclin molecules and binding with Cdk inhibitor proteins (AdvancedCancer Research, Vol. 66, pp181-212(1995); Current Opinion in CellBiology, Vol. 7, pp773-780(1995): Nature, Vol. 374, pp 131-134 (1995)).

Cdk inhibitor proteins in a mammalian cell are classified roughly intotwo kinds due to the differences in structure and property; Cip/Kipfamily and INK4 family. The former inhibits cyclin-Cdk complex widely,while the latter binds with Cdk4 or Cdk6, thereby specificallyinhibiting cyclin-Cdk complex (Nature, vol. 366, pp704-707(1993);Molecular and Cellular Biology, vol. 15, pp2627-2681(1995): Genes andDevelopment, vol. 9, pp1149-1163 (1995)).

For example, P21(Sdi1/Cip1/Waf1) is nominated for a representativeexample of the former, of which RNA transcription is induced by a cancerrepressor gene product, p53.

On the other hand, for example, p16 (INK4a/MTS1/CDK4I/CDKN2) is one ofthe Cdk inhibitor proteins belonging to the latter. The P16 gene islocated on the human chromosome 9p21 which are found to be abnormal witha high frequency in human cancer cells. Actually, many cases of deletionof the p16 gene have been reported in clinical patients. Also,high-frequency of tumorigenesis in a p16 knockout-mouse has beenreported (Nature Genetics, vol. 8, pp27-32(1994); Trends in Genetics,vol. 11, pp136-140(1995); Cell, vol. 85, pp27-37(1996)).

Each Cdk regulates the progression of cell cycle by phosphorylation of acertain target protein in a specific phase of cell cycle, and above all,the retinoblastoma (RB) protein is considered to be one of the mostimportant target proteins. The RB protein plays an important role inprogression from G1 phase to S phase and is rapidly phosphorylatedduring the term from late G1 phase to initial S phase. It is consideredthat this phosphorylation is carried out by cyclin D-Cdk4/Cdk6 complexfollowed by cyclin E-Cdk2 complex, following progression of cell cycle.The complex composed of hypophosphorylated RB and transcription factorE2F in early G1 phase dissociates when the RB protein becomeshyperphosphorylated. As a result, E2F becomes a transcriptionalactivator, and at the same time, the suppression of the promoteractivity by RB-E2F complex is removed, thus leading to the activation ofE2F dependent transcription. At present, the Cdk-RB pathway consistingof E2F, its suppressor RB protein, Cdk4/Cdk6 which repressivelyregulates the function of RB protein, Cdk inhibitory protein whichcontrols the kinase activity of Cdk4/Cdk6, and D-type cyclin is thoughtto be an important mechanism to regulate the progression from G1 phaseto S phase (Cell, vol. 58, pp1097-1105(1989); Cell, vol. 65,pplO53-1061(1991); Oncogene, vol. 7, pp1067-1074(1992); Current Opinionin Cell Biology, Vol. 8, pp805-814(1996); Molecular and CellularBiology, vol. 18, pp753-761(1998)). In fact, E2F-binding DNA sequence islocated, for example, upstream of the sequence of many cellgrowth-related genes which are important in S phase, and it is reportedthat in several genes among them the transcription is activated in anE2F-dependent manner during the term from late G1 phase to initial Sphase (The EMBO Journal, vol. 9, pp2179-2184, (1990); Molecular andCellular Biology, vol. 13, pp1610-1618 (1993)).

Abnormalities of any factors which relates to in the Cdk-RB pathway suchas, for example, deletion of functional pl6, high expression of cyclinD1, high expression of Cdk4 and deletion of functional RB protein arefrequently found in human cancer cells (Science, vol. 254,pp1138-1146(1991); Cancer Research, Vol. 53, pp5535-5541 (1993); CurrentOpinion in Cell Biology, Vol. 8, pp805-814(1996). These are abnormal tosuch an extent that they tend to promote the progression from G1 phaseto S phase, and thus it is obvious that this pathway plays an importantrole in malignant alteration or abnormal growth of cancer cells.

Previously, as known compounds having an inhibitory activity on Cdkfamily, a series of chromone derivatives represented, for example, byflavopiridol are known (WO 97/16447, 98/13344); however, the inhibitoryactivity of those chromone derivatives is not sufficient.

DISCLOSURE OF THE INVENTION

The present inventors previously prepared a novel pyrazinone derivativehaving inhibitory activity against Cdk, and filed a PCT internationalapplication (PCT/JP01/05545; WO 02/02550).

Although the above pyrazinone derivative showed Cdk inhibitory activity,its cell growth-inhibitory activity was not sufficient.

Therefore, a compound with a novel basic structure having an excellentcell growth-inhibitory activity as well as inhibitory activity againstCdK is now desired.

The present inventors conducted intensive studies in order to provide anovel compound having an excellent cell growth-inhibitory activity aswell as CdK inhibitory activity. As a result, we found that a novelquinoxalinone derivative has both an inhibitory activity against Cdk andcell growth-inhibitory activity, and thus completed the presentinvention. It is obvious that the quinoxalinone derivative of thepresent invention has completely structural originality as compared tothe above pyrazinone derivati ve in light of its cyclic structurecontaining a quinoxalinone core structure.

Thus, the present invention relates to a quinoxalinone derivative of theformula (I):

or a pharmaceutically acceptable salt or ester thereof, wherein;

-   -   X is NH, S, O or CH₂;    -   Y is O or NR′, wherein R′ is hydrogen or lower alkyl;    -   the partial structure        is selected from the following formula:        wherein B₁, B₂, . . . , B_(n-1) and B_(n), and B′₁, B′₂, . . . ,        B′_(n-1) and B′_(n) (in which n is 4, 5 or 6) are each defined        as follows:

B₁, B₂, . . . , B_(n-1) and B_(n) are each independently C, CH, CRO, Nor O (wherein

-   -   when B₁, B₂, . . . , B_(n-1) and B_(n) are each independently C,        then B′₁, B′₂, . . . , B′_(n-1) and B′_(n) are oxo,        respectively;    -   when B₁, B₂, . . . , B_(n-1) and B_(n) are each independently O,        then B′₁, B′₂, . . . , B_(n-1) and B′_(n) are each taken        together with B₁, B₂, . . . , B_(n-1) and B_(n), respectively,        to form O, with the proviso that two or more members of B₁, B₂ .        . . , B_(n-1) and B_(n), at the same time, are not taken        together with B′₁, B′₂, . . . , B′_(n-1) and B′_(n),        respectively, to form O; and    -   R₀ is lower alkyl), and    -   B′₁, B′₂, . . . , B′_(n-1) and B′_(n) are each independently        hydrogen, halogen, hydroxy, oxo, lower alkoxy, amino, lower        alkylamino, di-lower alkylamino, lower alkyl or lower alkenyl        (wherein    -   said lower alkyl and said lower alkenyl may be substituted with        one or more, same or different substituents selected from the        group consisting of hydroxy, lower alkoxy, amino and lower        alkylamino, and    -   among B′₁, B′₂, . . . , B′_(n-1) and B′_(n), B′_(i) and B′_(i+2)        (in which i is 1, 2 or 3) taken together with B_(i), B_(i+1) and        B_(i+2), or B′_(i) and B′_(i+3) (in which i is 1 or 2) taken        together with B_(i), B_(i+1), B_(i+2) and B_(i+3), may form a        cycloalkyl having five to six carbon atoms or an aliphatic        heterocyclic group selected from <substituent group β₁>, and        said cycloalkyl and said aliphatic heterocyclic group may be        substituted with one or more, same or different substituents        selected from lower alkyl and <substituent group α>);    -   R is hydrogen, lower alkyl, lower alkenyl, amino of which        nitrogen is di-substituted with R_(a) and R_(b), amino-lower        alkyl of which nitrogen is di-substituted with R_(a) and R_(b),        or L, wherein R_(a) and R_(b) are each independently hydrogen,        lower alkyl, lower alkoxyalkyl or halogenated lower alkyl, and L        is L₁-L₂-L₃(wherein L₁ is a single bond, —(CH₂)_(k1)—,        —(CH₂)_(k1)—O— or —(CH₂)_(k1)—NH— (in which k1 is an integer of        1 to 3); L₂ is a single bond or —(CH₂)_(k2)— (in which k2 is an        integer of 1 to 3); and L₃ is lower alkyl, lower alkoxy,        cycloalkyl having three to six carbon atoms, phenyl, pyridyl,        pyrrolidinyl or piperidinyl, said lower alkyl, lower alkoxy,        cycloalkyl having three to six carbon atoms, phenyl, pyridyl,        pyrrolidinyl or piperidinyl being optionally substituted with        one or more fluorine atoms); or    -   a substituent selected from <substituent group α>, which may be        substituted with one or more, same or different substituents        selected from <substituent group γ>, or lower alkyl substituted        with said substituent; or    -   a cyclic group selected from <substituent group β₂>, which may        be substituted with one or more, same or different substituents        selected from a lower alkyl, <substituent group α>and        <substituent group γ>, and also may be substituted with J        (wherein J is J₁-J₂-J₃; J₁ is a single bond, —C(═O)—, —O—, —NH—,        —NHCO—, —(CH₂)_(k3)— or —(CH₂)_(k3)—O— (in which k₃ is an        integer of 1 to 3); J₂ is a single bond or —(CH₂)_(k4)— (in        which k₄ is an integer of 1 to 3); and J₃ is lower alkyl, lower        alkoxy, —CONR_(a)R_(b) (wherein R_(a) and R_(b) each have the        same meaning as defined above), phenyl, pyridyl, pyrrolidinyl or        piperidinyl, said lower alkyl, lower alkoxy, phenyl, pyridyl,        pyrrolidinyl or piperidinyl being optionally substituted with        one or more fluorine atoms), or lower alkyl substituted with        said cyclic group, and    -   in the above, <substituent group α>, <substituent group β₁>,        <substituent group β₂>and <substituent group γ> each have the        meaning shown below:

<substituent group α> hydroxy, hydroxy-lower alkyl, cyano, halogen,carboxyl, lower alkanoyl, loweralkoxycarbonyl, loweralkoxy,loweralkoxyalkyl, amino, lower alkylamino, lower alkylsulfonyl,halogenated lower alkyl, halogenatedlower alkoxy, halogenatedloweralkylamino, nitro and lower alkanoylamino,

<substituent group β₁>

<substituent group β₂>

<substituent group γ>cycloalkyl having three to six carbon atoms, lower alkyl substitutedwith cycloalkyl having three to six carbon atoms, phenyl, lower alkylsubstituted with phenyl, pyridyl, pyrrolidinyl and piperidinyl, whereinsaid cycloalkyl having three to six carbon atoms, phenyl, pyridyl,pyrrolidinyl and piperidinyl may be substituted with one or morefluorine atoms.

The symbols and terms described in the present specification arehereinafter explained.

The term “lower alkyl” in the above formula (I) refers to a straight- orbranched-chain alkyl group having one to six carbon atoms; for example,methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,tert-butyl, pentyl, hexyl or the like; preferably methyl, ethyl, propyl,isopropyl, tert-butyl or pentyl; particularly preferably methyl.

The term “lower alkenyl” in the above formula (I) refers to a straight-or branched-chain alkenyl group having two to six carbon atoms; forexample, vinyl, 1-propenyl, allyl, isopropenyl, 1-butenyl, 3-butenyl,1,3-butanedienyl, 2-pentenyl, 4-pentenyl, 1-hexenyl, 3-hexenyl,5-hexenyl or the like; preferably 1-propenyl.

The term “halogen” in the above formula (I) refers to, for example,fluorine atom, chlorine atom, bromine atom, iodine atom or the like;preferably fluorine atom, chlorine atom or bromine atom; more preferablyfluorine atom.

The term “lower alkoxy” in the above formula (I) refers to a group inwhich oxygen atom is substituted with “lower alkyl”; concretely forexample, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy,sec-butoxy, tert-butoxy, pentyloxy, neopentyloxy, hexyloxy, isohexyloxyor the like; preferably methoxy, ethoxy, isopropyloxy or tert-butoxy;more preferably methoxy or ethoxy, particularly preferably methoxy.

The term “lower alkoxyalkyl” in the above formula (I) refers to theabove “lower alkyl” substituted with the above “lower alkoxy”; forexample, methoxymethyl, ethoxymethyl, isopropoxymethyl, butoxymethyl,isobutoxymethyl, sec-butoxymethyl, tert-butoxymethyl, pentyloxymethyl,neopentyloxymethyl, hexyloxymethyl, isohexyloxymethyl, 1-methoxyethyl,1-ethoxyethyl, 1-isopropoxyethyl, 1-butoxyethyl, 1-isobutoxyethyl,1-sec-butoxyethyl, 1-tert-butoxyethyl, 1-pentyloxyethyl,1-neopentyloxyethyl, 1-hexyloxyethyl, 1-isohexyloxyethyl,2-methoxyethyl, 2-ethoxyethyl, 2-isopropoxyethyl, 2-butoxyethyl,2-isobutoxyethyl, 2-sec-butoxyethyl, 2-tert-butoxyethyl,2-pentyloxyethyl, 2-neopentyloxyethyl, 2-hexyloxyethyl,2-isohexyloxyethyl, 1-methoxy-1-methylethyl, 1-ethoxy-1-methylethyl,1-isopropoxy-1-methylethyl, 1-butoxy-1-methylethyl,1-isobutoxy-1-methylethyl, 1-sec-butoxy-1-methylethyl,1-tert-butoxy-1-methylethyl, 1-pentyloxy-1-methylethyl,1-neopentyloxy-1-methylethyl, 1-hexyloxy-1-methylethyl,1-isohexyloxy-1-methylethyl or the like; preferably, for example,methoxymethyl, ethoxymethyl or isopropoxymethyl; particularly preferablymethoxymethyl.

The term “halogenated lower alkyl” in the above formula (I) refers to“lower alkyl” substituted with “halogen”; preferably “lower alkyl”substituted with one to three fluorine atoms; more preferably “loweralkyl” substituted with three fluorine atoms. Concrete examples thereofinclude trifluoromethyl, difluoromethyl, 2,2,2-trifluoroethyl,pentafluoroethyl and the like; preferably trifluoromethyl.

The term “halogenated lower alkoxy” in the above formula (I) refers to“lower alkoxy” substituted with “halogen”; preferably “lower alkoxy”substituted with one to three fluorine atoms; more preferably “loweralkoxy” substituted with three fluorine atoms. Concrete examples thereofinclude trifluoromethoxy, difluoromethoxy, 2,2,2-trifluoroethoxy,pentafluoroethoxy and the like; preferably trifluoromethoxy.

The term “lower alkoxycarbonyl” in the above formula (I) refers to acarbonyl group substituted with the above “lower alkoxy”; concretely forexample, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl,isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl,sec-butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl,neopentyloxycarbonyl, hexyloxycarbonyl, isohexyloxycarbonyl or the like,preferably methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl ortert-butoxycarbonyl; more preferably methoxycarbonyl or ethoxycarbonyl;particularly preferably methoxycarbonyl.

The term “lower alkanoyl” in the above formula (I) refers to a carbonylgroup substituted with the above “lower alkyl”; for example, acetyl,propionyl, butyryl, isobutyryl, pivaloyl or the like; preferably acetyl.

The term “lower alkylamino” in the above formula (I) refers to an aminogroup which is N-substituted with the above “lower alkyl”; for example,N-methylamino, N-ethylamino, N-propylamino, N-isopropylamino,N-butylamino, N-isobutylamino, N-tert-butylamino, N-pentylamino,N-hexylamino or the like; preferably, for example, N-methylamino,N-ethylamino, N-butylamino or N-tert-butylamino, particularly preferablyN-tert-butylamino.

The term “halogenated lower alkylamino” in the above formula (I) refersto “lower alkylamino” substituted with “halogen”; preferably “loweralkylamino” substituted with one to three fluorine atoms; morepreferably “lower alkylamino” substituted with three fluorine atoms.Concrete examples thereof include 2,2,2-trichloroethyl,2,2,2-trifluoroethyl and the like; particularly preferably2,2,2-trifluoroethyl.

The term “di-lower alkylamino” in the above formula (I) refers to anamino group which is N,N-disubstituted with the above “lower alkyl”; forexample, N,N-dimethylamino, N,N-diethylamino, N,N-dipropylamino,N,N-diisopropylamino, N,N-dibutylamino, N,N-diisobutylamino,N,N-di-tert-butylamino, N,N-dipentylamino, N,N-dihexylamino,N-ethyl-N-methylamino, N-methyl-N-propylamino or the like; preferably,for example, N,N-dimethylamino, N,N-diethylamino, N,N-dibutylamino,N-ethyl-N-methylamino or N-methyl-N-propylamino.

The term “lower alkylsulfonyl” in the above formula (I) refers to asulfonyl group substituted with the above “lower alkyl”; for example,methylsulfonyl, ethylsulfonyl, butylsulfonyl or the like; preferably,for example, methylsulfonyl or ethylsulfonyl; particularly preferablymethylsulfonyl.

The term “cycloalkyl having three to six carbon atoms” in the aboveformula (I) refers to cyclopropyl, cyclobutyl, cyclopentyl orcyclohexyl, preferably cyclopropyl or cyclopentyl. The term “cycloalkylhaving five to six carbon atoms” in the above formula (I) refers tocyclopentyl or cyclohexyl, preferably cyclopentyl.

The term “hydroxy-lower alkyl” in the above formula (I) refers to theabove “lower alkyl” substituted with a hydroxy group; preferably “loweralkyl” substituted with one to three hydroxy groups; particularlypreferably “lower alkyl” substituted with one hydroxy group. Concreteexamples thereof include hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl,1-hydroxypropyl, 2-hydroxypropyl, 3-hydroxypropyl,1-hydroxy-2-methylethyl, 1-hydroxybutyl, 1-hydroxy-2-methylpropyl,1-hydroxy-2,2-dimethylethyl, 1-hydroxypentyl, 1-hydroxy-2-methylbutyl,1-hydroxyhexyl, 1-hydroxy-2-methylpentyl and the like; preferablyhydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl and1-hydroxy-2-methylethyl.

The term “amino-lower alkyl” in the above formula (I) refers to theabove “lower alkyl” substituted with an amino group; concretely forexample, aminomethyl, 1-amino, 2-aminoethyl, 1-aminopropyl,2-aminopropyl, 3-aminopropyl, 1-amino-2-methylethyl, 1-aminobutyl,1-amino-2-methylpropyl, 1-amino-2,2-dimethylethyl, 1-aminopentyl,1-amino-2-methylbutyl, 1-aminohexyl, 1-amino-2-methylpentyl or the like,preferably aminomethyl, 1-aminoethyl, 2-aminoethyl, or1-amino-2-methylethyl.

The term “lower alkanoyl” in the above formula (I) refers to a carbonylgroup substituted with the above “lower alkyl”; preferably a carbonylgroup substituted with an alkyl group having one to five carbon atoms.Concrete examples thereof include acetyl, propionyl, butyryl,isobutyryl, valeryl, isovaleryl, pivaloyl, pentanoyl and the like;preferably acetyl, propionyl and pivaloyl; particularly preferablyacetyl.

The term “lower alkanoylamino” in the above formula (I) refers to anamino group substituted with the above “lower alkanoyl”; for example,N-acetylamino, N-propionylamino, N-butyrylamino or the like; preferably,for example, N-acetylamino or N-propionylamino.

“Cdk”refers to a cyclin-dependent kinase including Cdk2, Cdc2(=Cdk1),Cdk4, Cdk6, Cdk7 and the like. Here, Cdk2 is cyclin-dependent kinase 2,Cdc2 is a cell division cycle 2, Cdk1 is a cyclin-dependent kinase 1,Cdk4 is a cyclin-dependent kinase 4, Cdk6 is a cyclin-dependent kinase6, and Cdk7 is a cyclin-dependent kinase 7. The term “Cdk inhibitor”means an inhibitor against a cyclin-dependent kinase including Cdk2,Cdc2, Cdk4, Cdk6, Cdk7 and the like.

The aforementioned term “pharmaceutically acceptable salt or esterthereof” is explained later.

BEST MODE FOR CARRYING OUT THE INVENTION

The embodiments of the compound of the formula (I) will be described inmore detail below.

X is NH, S, O or CH₂; preferably NH or S; particularly preferably NH.

Y is O or NR′ (wherein R′ is hydrogen or lower alkyl), preferably O.

The partial structure

is selected from the following formula:

preferably the following formula:

more preferably the following formula:

The above B₁, B₂, . . . , B_(n-1) and B_(n), and B′₁, B′₂, . . . ,B′_(n-1) and B′_(n) (in which n is 4, 5 or 6) are explained below. Inthe above formula (I), B₁, B₂, . . . , B_(n-1) and B_(n), and B′₁, B′₂,. . . , B′_(n-1) and B′_(n) (in which n is 4, 5 or 6) mean B₁, B₂, B₃and B₄, and B′₁, B′₂, B′₃ and B′₄ when n=4; B₁, B₂, B₃, B₄ and B₅, andB′₁, B′₂, B′₃, B′₄ and B′₅ when n=5; B₁, B₂, B₃, B₄, B₅ and B₆, and B′₁,B′₂, B′₃, B′₄, B′₅ and B′6 when n=6, respectively.

B₁, B₂, . . . , B_(n-1) and B_(n) are each independently C, CH, CR₀, Nor O, wherein R₀ is lower alkyl, and

-   -   when the partial structure        is the formula:        then preferably B₁, B₂, B₃, B₄ and B₅ are each independently CH;        or B₁, B₂, B₄ and B₅ are each independently CH and B₃ is N or O;        particularly preferably, B₁, B₂, B₄ and B₅ are each        independently CH and B₃ is N, and    -   when the partial structure        is the formula:        then preferably B₁, B₂, B₃, B₅ and B₆ are each independently CH        and B₄ is N.

Also, when at least one carbon atom of B₁, B₂, B₃, B₄ and B₅ is anasymmetric carbon, a compound of the above formula (I) includes anyoptical isomer thereof as well as a racemate thereof.

In the above B₁, B₂, . . . , B_(n-1) and B_(n),

-   -   when B₁, B₂, . . . , B_(n-1) and B_(n) are each independently C,        then B′₁, B′₂, . . . , B′_(n-1) and B′_(n) are oxo,        respectively;    -   when B₁, B₂, . . . , B_(n-1) and B_(n) are each independently O,        then B′₁, B′₂, . . . , B′_(n-1) and B′_(n) are each taken        together with B₁, B₂, . . . , B_(n-1) and B_(n), respectively,        to form O, with the proviso that two or more members of B₁, B₂,        . . . , B_(n-1) and B_(n), at the same time, are not taken        together with B′₁, B′₂, . . . , B′_(n-1) and B′_(n),        respectively, to form O.

B′₁, B′₂, . . . , B′_(n-1) and B′_(n) are each independently hydrogen,halogen, hydroxy, oxo, lower alkoxy, amino, lower-alkyl amino,di-lower-alkylamino, lower alkyl or lower alkenyl, wherein B′₁, B′₂, . .. , B′_(n-1) and B′_(n) are each independently taken together with B₁,B₂, . . . B_(n-1) and B_(n), respectively, to form 0, with the provisothat two or more members of B′₁, B′₂, . . . , B′_(n-1) and B′_(n), atthe same time, are not taken together with B₁, B₂, . . . , B_(n-1) andB_(n), respectively, to form O.

In the above B′₁, B′₂, . . . , B′_(n-1) and B′_(n), said lower alkyl andsaid lower alkenyl may be substituted with one or more, same ordifferent substituents selected from the group consisting of hydroxy,lower alkoxy, amino and lower alkylamino.

Also, among the above B′₁, B′₂, . . . , B′_(n-1) and B′_(n), B′_(i) andB′_(i+2) (in which i is 1, 2 or 3) taken together with B_(i), B_(i+1)and B_(i+2), or B′_(i) and B′_(i+3) (in which i is 1 or 2) takentogether with B_(i), B_(i+1), B_(i+2) and B_(i+3), may form a cycloalkylhaving five to six carbon atoms or an aliphatic heterocyclic groupselected from the group consisting of

(hereinafter referred to as <substituent group β₁>), and said cycloalkyland said aliphatic heterocycle may be substituted with one or more, sameor different substituents selected from the group consisting of hydroxy,hydroxy-lower alkyl, cyano, halogen, carboxyl, lower alkanoyl, loweralkoxycarbonyl, lower alkoxy, lower alkoxyalkyl, amino, loweralkylamino, lower alkylsulfonyl, halogenated lower alkyl, halogenatedlower alkoxy, halogenated lower alkylamino, nitro and loweralkanoylamino (hereinafter referred to as <substituent group α>) andlower alkyl.

Moreover, in the above B′₁, B′₂, . . . , B′_(n-1) and B′_(n), when thepartial structure

is the formula:

then preferably

-   -   all of B′₁, B′₂, B′₃, B′₄ and B′₅ are hydrogen; or    -   one of B′₁, B′₂, B′₃, B′₄ and B′₅ is lower alkyl or lower        alkenyl, and all the others are hydrogen; or    -   at least two of B′₁, B′₂, B′₃, B′₄ and B′₅ are each        independently lower alkyl or lower alkenyl, and all the others        are hydrogen; or among B′₁, B′₂, B′₃, B′₄ and B′₅, B′_(i) and        B′_(i+2) (in which i is 1, 2 or 3) taken together with B_(i),        B_(i+1) and B_(i+2), form an aliphatic heterocycle selected from        the group of        (hereinafter referred to as <substituent group β_(1a)>), wherein        said aliphatic heterocycle may be substituted with one or more,        same or different substituents selected from the group        consisting of hydroxy, hydroxy-lower alkyl, halogen, lower        alkoxycarbonyl, lower alkoxy, lower alkoxyalkyl, lower        alkylamino, methyl substituted with one to three fluorine atoms,        methoxy substituted with one to three fluorine atoms and lower        alkylamino substituted with one to three fluorine atoms        (hereinafter referred to as <substituent group α_(a)>) and lower        alkyl, and the others are hydrogen, lower alkyl or lower        alkenyl; more preferably,    -   B₁, B₂, B₄ and B₅ are each independently CH, B₃ is N, and all of        B′₁, B′₂, B′₃, B′₄ and B′₅ are hydrogen; or    -   one of B′₁, B′₂, B′₃, B′₄ and B′₅ is lower alkyl or lower        alkenyl, and all the others are hydrogen; or    -   at least two of B′₁, B′₂, B′₃, B′₄ and B′₅ are each        independently lower alkyl or lower alkenyl, and all the others        are hydrogen; or    -   among B′₁, B′₂, B′₃, B′₄ and B′₅, B′_(i) and B′_(i+2) (in which        i is 1, 2 or 3) taken together with B_(i), B_(i+1) and B_(i+2),        form an aliphatic heterocycle selected from <substituent group        β_(1a)>, wherein said aliphatic heterocycle may be substituted        with one or more, same or different substituents selected from        lower alkyl and <substituent group α_(a)>, and the others are        hydrogen, lower alkyl or lower alkenyl;        particularly preferably,    -   X is NH;    -   B₁, B₂, B₄ and B₅ are each independently CH and B₃ is N;    -   among B′₁, B′₂, B′₃, B′₄ and B′₅, B′_(i) and B′_(i+2) (in which        i is 1) taken together with B_(i), B_(i+1) and B_(i+2) form an        aliphatic heterocycle selected from <substituent group β_(1a)>,        wherein said aliphatic heterocycle may be substituted with lower        alkyl, and the others are hydrogen.

Furthermore, in the above B′₁, B′₂, . . . , B′_(n-1) and B′_(n), whenthe partial structure

is the formula:

then preferably B′_(i) and B′_(i+3) (in which i is 1 or 2) among B′₁,B′₂, B′₃, B′₄, B′₅ and B′₆, taken together with B_(i), B_(i+1), B_(i+2)and B_(i+3), form

-   -   and all the others are hydrogen;        more preferably B′₁, B′₂, B′₃, B′₅ and B′₆ are each        independently CH, B₄ is N, and B′_(i) and B′_(i+3) (in which i        is 1 or 2) among B′₁, B′₂, B′₃, B′₄, B′₅ and B′₆, taken together        with B_(i), B_(i+1), B_(i+2) and B_(i+3), form        and all the others are hydrogen.

The partial structure

includes, for example,

wherein R″ is hydrogen or methyl,more preferably

particularly preferably

As mentioned above, in terms of improvement in solubility of compoundsof the formula (I), it is preferable that any one of B₁, B₂, . . . ,B_(n-1) and B_(n) is a nitrogen atom.

R is hydrogen, lower alkyl, lower alkenyl, amino of which nitrogen isdi-substituted with R_(a) and R_(b), amino-lower alkyl of which nitrogenis di-substituted with R_(a) and R_(b), or L, wherein R_(a) and R_(b)are each independently hydrogen, lower alkyl, lower alkoxyalkyl orhalogenated lower alkyl; and L is L₁-L₂-L₃ (wherein L₁ is a single bond,—(CH₂)_(k1)—, —(CH₂)_(k1)—O— or —(CH₂)_(k1)—NH— (in which k1 is aninteger of 1 to 3); L₂ is a single bond or —(CH₂)_(k2)— (in which k2 isan integer of 1 to 3); and L₃ is lower alkyl, lower alkoxy, cycloalkylhaving three to six carbon atoms, phenyl, pyridyl, pyrrolidinyl orpiperidinyl, said L₃ is lower alkyl, lower alkoxy, cycloalkyl havingthree to six carbon atoms, phenyl, pyridyl, pyrrolidinyl or piperidinylbeing optionally substituted with one or more fluorine atoms); or

-   -   a substituent selected from <substituent group α> which may be        substituted with one or more, same or different substituents        selected from the group consisting of cycloalkyl having three to        six carbon atoms, lower alkyl substituted with cycloalkyl having        three to six carbon atoms, phenyl, lower alkyl substituted with        phenyl, pyridyl, pyrrolidinyl and piperidinyl, said cycloalkyl        having three to six carbon atoms, phenyl, pyridyl, pyrrolidinyl        and piperidinyl being optionally substituted with one or more        fluorine atoms (hereinafter referred to as <substituent group        γ>, or lower alkyl substituted with said substituent; or    -   a cyclic group selected from the group consisting of        (hereinafter referred to as <substituent group β₂>), wherein        said cyclic group may be substituted with one or more, same or        different substituents selected from lower alkyl, <substituent        group α>and <substituent group γ>, and also may be substituted        with J. Here, J is J₁-J₂-J₃, wherein J₁ is a single bond,        —C(═O)—, —O—, —NH—, —NHCO—, —(CH₂)_(k3)— or —(CH₂)_(k3)—O— (in        which k3 is an integer of 1 to 3); J₂ is a single bond or        —(CH₂)_(k4)— (in which k4 is an integer of 1 to 3); and J₃ is        lower alkyl, lower alkoxy, —CONR_(a)R_(b) (wherein R_(a) and        R_(b) each has the same meaning as defined above), phenyl,        pyridyl, pyrrolidinyl or piperidinyl, said lower alkyl, lower        alkoxy, phenyl, pyridyl, pyrrolidinyl or piperidinyl being        optionally substituted with one or more fluorine atoms, or lower        alkyl substituted with said cyclic group.

In addition, R is preferably hydrogen, amino-lower alkyl of whichnitrogen is di-substituted with R_(a) and R_(b), or L, wherein R_(a) andR_(b) are each independently lower alkyl, and L is L₁-L₂-L₃ (wherein L₁is a single bond, —(CH₂)_(k1)—, —(CH₂)_(k1)—O— or —(CH₂)_(k1)—NH—(inwhich k1 is 1 or 2); L₂ is a single bond or —(CH₂)_(n)— (in which k2 is1 or 2); and L₃ is lower alkoxy or cycloalkyl having three to six carbonatoms); or

-   -   a cyclic group selected from <substituent group β₂>which may be        substituted with one or more, same or different substituents        selected from lower alkyl and <substituent group α>, or lower        alkyl substituted with said cyclic group, wherein <substituent        group β₂>is selected from        and <substituent group α>is selected from halogen, lower alkoxy,        lower alkoxyalkyl, methyl substituted with one to three fluorine        atoms and methoxy substituted with one to three fluorine atoms;        or    -   lower alkyl substituted with a substituent selected from the        group consisting of lower alkylamino and lower alkylamino        substituted with one to three fluorine atoms.

The above R binds to the quinoxalinone structure preferably as describedin the following formula:

The above R includes, for example,

and the like; preferably includes

more preferably includes

The present invention relating to a compound of the formula (I),including a pharmaceutically acceptable salt or ester thereof, may alsobe described as follows.

-   -   (i) A quinoxalinone derivative of the formula (I):        or a pharmaceutically acceptable salt or ester thereof, wherein;    -   X is NH, S, O or CH₂;    -   Y is O or NR′, wherein R′ is hydrogen or lower alkyl;    -   the partial structure        is selected from the following formula:    -   wherein B₁, B₂, . . . , B_(n-1) and B_(n), and B′₁, B′₂, . . . ,        B′_(n-1) and B′_(n) (in which n is 4, 5 or 6) are each defined        as follows:    -   B₁, B₂, . . . , B_(n-1) and B_(n) are each independently C, CH,        CR₀, N or O (wherein    -   when B₁, B₂, . . . , B_(n-1) and B_(n) are each independently C,        then B′₁, B′₂, . . . , B′_(n-1) and B′_(n) are oxo,        respectively;    -   when B₁, B₂, . . . , B_(n-1) and B_(n) are each independently O,        then B′₁, B′₂, . . . , B′_(n-1) and B′_(n) are each taken        together with B₁, B₂, . . . , B_(n-1) and B_(n), respectively,        to form O, with the proviso that two or more members of B₁, B₂,        . . . , B_(n-1) and B_(n), at the same time, are not taken        together with B′₁, B′₂, . . . , B′_(n-1) and B′_(n),        respectively, to form O; and    -   R₀ is lower alkyl), and    -   B′₁, B′₂, . . . , B′_(n-1) and B′_(n) are each independently        hydrogen, halogen, hydroxy, oxo, lower alkoxy, amino, lower        alkylamino, di-lower alkylamino, lower alkyl or lower alkenyl        (wherein    -   said lower alkyl and said lower alkenyl may be substituted with        one or more, same or different substituents selected from the        group consisting of hydroxy, lower alkoxy, amino and lower        alkylamino, and    -   among B′₁, B′₂, . . . , B′_(n-1) and B′_(n), B′_(i) and B′_(i+2)        (in which i is 1, 2 or 3) taken together with B_(i), B_(i+1) and        B_(i+2), or B′_(i) and B′_(i+3) (in which i is 1 or 2) taken        together with B_(i), B_(i+1), B_(i+2) and B_(i+3), may form a        cycloalkyl having five to six carbon atoms or an aliphatic        heterocyclic group selected from <substituent group β₁>, and        said cycloalkyl and said aliphatic heterocyclic group may be        substituted with one or more, same or different substituents        selected from lower alkyl and <substituent group α>);    -   R is hydrogen, lower alkyl, lower alkenyl, amino in which the        nitrogen atom is di-substituted with R_(a) and R_(b),        amino-lower alkyl in which the nitrogen atom is di-substituted        with R_(a) and R_(b), or L, wherein R_(a) and R_(b) are each        independently hydrogen, lower alkyl, lower alkoxyalkyl or        halogenated lower alkyl, and L is L₁-L₂-L₃ (wherein L₁ is a        single bond, —(CH₂)_(k1)—, —(CH₂)_(k1)—O— or —(CH₂)_(k1)—NH— (in        which k1 is an integer of 1 to 3); L₂ is a single bond or        —(CH₂)_(k2)— (in which k2 is an integer of 1 to 3); and L₃ is        lower alkyl, lower alkoxy, cycloalkyl having three to six carbon        atoms, phenyl, pyridyl, pyrrolidinylorpiperidinyl, said lower        alkyl, lower alkoxy, cycloalkyl having three to six carbon        atoms, phenyl, pyridyl, pyrrolidinyl or piperidinyl being        optionally substituted with one or more fluorine atoms); or    -   a substituent selected from <substituent group α>, which may be        substituted with one or more, same or different substituents        selected from <substituent group γ>, or lower alkyl substituted        with said substituent; or    -   a cyclic group selected from <substituent group β₂>, which may        be substituted with one or more, same or different substituents        selected from a lower alkyl, <substituent group α>and        <substituent group γ>, and also may be substituted with J        (wherein J is J₁-J₂-J₃; J₁ is a single bond, —C(═O)—, —O—, —NH—,        —NHCO—, —(CH₂)_(k3)— or —(CH₂)_(k3)—O— (in which k3 is an        integer of 1 to 3); J₂ is a single bond or —(CH₂)_(k4)— (in        which k4 is an integer of 1 to 3); and J₃ is lower alkyl, lower        alkoxy, —CONR_(a)R_(b) (wherein R_(a) and R_(b) each have the        same meaning as defined above), phenyl, pyridyl, pyrrolidinyl or        piperidinyl, said lower alkyl, lower alkoxy, phenyl, pyridyl,        pyrrolidinyl or piperidinyl being optionally substituted with        one or more fluorine atoms), or lower alkyl substituted with        said cyclic group, and    -   in the above, <substituent group α>, <substituent group β₁>,        <substituent group β₂>and <substituent group γ>each have the        meaning shown below:

<substituent group α>

hydroxy, hydroxy-lower alkyl, cyano, halogen, carboxyl, lower alkanoyl,lower alkoxycarbonyl, lower alkoxy, lower alkoxyalkyl, amino, loweralkylamino, lower alkyl sulfonyl, halogenated lower alkyl, halogenatedlower alkoxy, halogenated lower alkylamino, nitro and loweralkanoylamino,

-   -   <substituent group β₁>    -   <substituent group β₂>        substituent group γ>        cycloalkyl having three to six carbon atoms, lower alkyl        substituted with cycloalkyl having three to six carbon atoms,        phenyl, lower alkyl substituted with phenyl, pyridyl,        pyrrolidinyl and piperidinyl, wherein said cycloalkyl having        three to six carbon atoms, phenyl, pyridyl, pyrrolidinyl and        piperidinyl may be substituted with one or more fluorine atoms;        or    -   (ii) The compound according to the above (i) or a        pharmaceutically acceptable salt or ester thereof, wherein;    -   X is NH or S; and    -   Y is O; or    -   (iii) The compound according to the above (ii) or a        pharmaceutically acceptable salt or ester thereof, wherein;    -   the partial structure        is the formula:    -   (iv) The compound according to the above (iii) or a        pharmaceutically acceptable salt or ester thereof, wherein;    -   B₁, B₂, B₃, B₄ and B₅ are each independently CH; or    -   B₁, B₂, B₄ and B₅ are each independently CH, and B₃ is N or O;        or    -   (v) The compound according to the above (iv) or a        pharmaceutically acceptable salt or ester thereof, wherein;    -   the <substituent group α> is selected from hydroxy,        hydroxy-lower alkyl, halogen, lower alkoxycarbonyl, lower        alkoxy, lower alkoxyalkyl, lower alkylamino, methyl substituted        with one to three fluorine atoms, methoxy substituted with one        to three fluorine atoms and lower alkylamino substituted with        one to three fluorine atoms, and the <substituent group β₁> is    -   (vi) The compound according to the above (v) or a        pharmaceutically acceptable salt or ester thereof, wherein;    -   B₁, B₂, B₄ and B₅ are each independently CH, B₃ is N, and all of        B′₁, B′₂, B′₃, B′₄ and B′₅ are hydrogen; or    -   one of B′₁, B′₂, B′₃, B′₄ and B′₅ is lower alkyl or lower        alkenyl, and all the others are hydrogen; or    -   at least two of B′₁, B′₂, B′₃, B′₄ and B′₅ are each        independently lower alkyl or lower alkenyl, and all the others        are hydrogen; or    -   among B′₁, B′₂, B′₃, B′₄ and B′₅, B′_(i) and B′_(i+2) (in which        i is 1, 2 or 3) taken together with B_(i), B_(i+1) and B_(i+2)        form an aliphatic heterocycle selected from <substituent group        β₁> (wherein said aliphatic heterocycle may be substituted with        one or more, same or different substituents selected from lower        alkyl and <substituent group α>), and the others are hydrogen,        lower alkyl or lower alkenyl; or    -   (vii) The compound according to the above (vi) or a        pharmaceutically acceptable salt or ester thereof, wherein;    -   X is NH;    -   B₁, B₂, B₄ and B₅ are each independently CH, and B₃ is N;    -   among B′₁, B′₂, B′₃, B′₄ and B′₅, B′_(i) and B′_(i+2) (in which        i is 1) taken together with B_(i), B_(i+1) and B_(i+2) form an        aliphatic heterocycle selected from <substituent group β₁>        (wherein said aliphatic heterocycle may be substituted with        lower alkyl), and the others are hydrogen; or    -   (viii) The compound according to the above (ii) or a        pharmaceutically acceptable salt or ester thereof, wherein;    -   the partial structure        is the formula:        wherein B₁, B₂, B₃, B₅ and B₆ are each independently CH, and B₄        is N; among B′₁, B′₂, B′₃, B′₄, B′₅ and B′₆, B′_(i) and B′_(i+3)        (in which i is 1 or 2) taken together with B_(i), B_(i+1),        B_(i+2) and B_(i+3) form        and all the others are hydrogen; or    -   (ix) The compound according to any one of the above (vi)        to (viii) or a pharmaceutically acceptable salt or ester        thereof, wherein the R binds to quinoxalinone as described in        the following formula:    -   (x) The compound according to the above (ix) or a        pharmaceutically acceptable salt or ester thereof, wherein;    -   R is hydrogen, amino-lower alkyl in which the nitrogen atom is        di-substituted with R_(a) and R_(b), or L, wherein R_(a) and        R_(b) are each independently lower alkyl, and L is L₁-L₂-L₃        (wherein L₁ is a single bond, —(CH₂)_(k1)—, —(CH₂)_(k1)—O— or        —(CH₂)_(k1)—NH— (in which k1 is an integer of 1 or 2; L₂ is a        single bond or —(CH₂)_(k2)— (in which k2 is an integer of 1 or        2); and L₃ is lower alkoxy or cycloalkyl having three to six        carbon atoms); or    -   a cyclic group selected from <substituent group β₂>, which may        be substituted with one or more, same or different substituents        selected from lower alkyl and <substituent group α>, or lower        alkyl substituted with said cyclic group, wherein the        <substituent group β₂>is selected from        and the <substituent group a>is selected from halogen, lower        alkoxy, lower alkoxyalkyl, methyl substituted with one to three        fluorine atoms, and methoxy substituted with one to three        fluorine atoms; or lower alkyl substituted with a substituent        selected from the group consisting of lower alkylamino and lower        alkylamino substituted with one to three fluorine atoms; or    -   (xi) The compound according to the above (ii) or a        pharmaceutically acceptable salt or ester thereof, wherein;    -   the partial structure        is selected from the group consisting of        wherein R″ is hydrogen or methyl; and    -   R is selected from the group consisting of        or    -   (xii) The compound according to the above (xi) or a        pharmaceutically acceptable salt or ester thereof, wherein;    -   X is NH; and    -   the partial structure        is the formula:        wherein R″ is methyl; or    -   (xiii) The compound according to the above (i) or a        pharmaceutically acceptable salt or ester thereof, wherein;    -   the quinoxalinone derivative is        (xiv) A pharmaceutical composition comprising one or more kinds        of the quinoxalinone derivative according to the above (i) as an        active ingredient, together with a pharmaceutically acceptable        carrier or diluent; or    -   (xv) A Cdk inhibitor comprising one or more kinds of the        quinoxalinone derivative according to the above (i) as an active        ingredient, together with a pharmaceutically acceptable carrier        or diluent; or    -   (xvi) An anti-cancer agent comprising one or more kinds of the        quinoxalinone derivative according to the above (i) as an active        ingredient, together with a pharmaceutically acceptable carrier        or diluent.

As mentioned above, in the compound of the formula (I):

wherein X, Y, n; the partial structure

B₁, B₂, . . . , B_(n-1) and B_(n); B′₁, B′₂, . . . , B′_(n-1) andB′_(n); R, <substituent group α>, <substituent group β₁>, <substituentgroup β₂>and <substituent group γ> each have the same meaning as definedabove, the partial structure

is selected from the following formula:

Therefore, the compound of the formula (I) may also be defined as thecompound of the formula (I):

wherein X, Y, n; B₁, B₂, . . . , B_(n-1) and B_(n); B′₁, B′₂, . . . ,B′_(n-1) and B′_(n); R, <substituent group α>, <substituent group β₁>,<substituent group β2>and <substituent group γ>each have the samemeaning as defined above.

On the basis of the above newly defined formula (I), a preparationmethod of the compound of the formula (I) is hereinafter described.

The compound of the formula (I):

wherein X, Y, n; B₁, B₂, . . . , B_(n-1) and B_(n); B′₁, B′₂, . . . ,B′_(n-1) and B′_(n); R, <substituent group α>, <substituent group β₁>,<substituent group β₂>and <substituent group γ> each have the samemeaning as defined above, can be prepared by removing a protecting groupfrom the compound of the below-mentioned formula (II) or (III):

wherein X, Y, n; B₁, B₂, . . . , B_(n-1) and B_(n); B′₁, B′₂, . . . ,B′_(n-1) and B′_(n); R, <substituent group α>, <substituent group β₁>,<substituent group β2>and <substituent group γ>each have the samemeaning as defined above, and PG is 4-methoxybenzyl,2,4-dimethoxybenzyl, benzyl, t-butyl, methyl, ethyl, methoxymethyl,2-(trimethylsilylethoxy)methyl or the like, preferably, methyl or2-(trimethylsilylethoxy)methyl, methoxymethyl. Removal of the protectinggroup can be carried out according to the method described in ProtectiveGroups in Organic Synthesis (T. W. Greene, John Wiley & Sons, Inc, 1981)or its analogous methods, such as solvolysis using an acid, though itdepends on the kind of protecting groups and the stability of compoundsused.

The preparation methods of the compounds of the formula (II) or (III):

are hereinafter described.Preparation Method A:

>The compound of the above formula (II) or (III) wherein Y is an oxygenatom can be prepared by subjecting the compound of the below formula(IV) or (V):

wherein X, Y, n; B₁, B₂, . . . , B_(n-1) and B_(n); B′₁, B′₂, . . . ,B′_(n-1) and B′_(n); R, <substituent group α>, <substituent group β₁>,<substituent group β₂>, <substituent group γ> and PG each have the samemeaning as defined above, to the Mitsunobu reaction for intramolecularcyclization (Synthesis, 1981, 1). For example, the compound of the aboveformula (II) or (III) can be prepared by reacting the compound of theabove formula (IV) or (V) with triphenylphosphine and diethylazodicarboxylate in a solvent such as tetrahydrofuran, 1,4-dioxan,methylene chloride, chloroform, toluene or the like. In this reaction,the reaction temperature is usually OC to room temperature, although itmay be appropriately chosen depending on the starting material or thereaction solvent to be used. Further, the reaction is usually completedwithin 1 to 24 hours, but the reaction time may be appropriatelyadjusted to make it longer or shorter.

The compound of the above formula (IV) can be prepared by removing theprotecting group represented by PG₂ or PG₃ from the compound of theformula (VI):

wherein n; B₁, B₂, . . . , B₁₋₁ and B_(n); B′₁, B′₂, . . . , B′_(n-1)and B′_(n); R, <substituent group α>, <substituent group β₁>,<substituent group β₂>and <substituent group γ> each have the samemeaning as defined above; PG₁, PG₂ and PG₃ are each a protecting group;PG₁ and PG₂ are the same or different and are each 4-methoxybenzyl,2,4-dimethoxybenzyl, benzyl, t-butyl, methyl, ethyl, methoxymethyl,2-(trimethylsilylethoxy)methyl, t-butyldimethylsilyl,t-butyldiphenylsilyl, acetyl, benzoyl, or the like, preferably methyl,2-(trimethylsilylethoxy)methyl or methoxymethyl; and PG₃ is hydrogen,4-methoxcybenzyl, 2,4-dimethoxybenzyl, benzyl, methoxymethyl,2-(trimethylsilylethoxy)methyl, t-butyldimethylsilyl,t-butyldiphenylsilyl, acetyl, benzoyl or the like, preferablyt-butyldimethylsilyl, t-butyldiphenylsilyl, acetyl or benzoyl.

Removal of the protecting group can be carried out according to themethod described in Protective Groups in Organic Synthesis (T. W.Greene, John Wiley & Sons, Inc, 1981) or its analogous methods such assolvolysis using an acid or a base, chemical reduction using a metalcomplex hydride, and catalytic reduction using a palladium carboncatalyst or Raney nickel catalyst, though it depends on the kind ofprotecting groups and the stability of compounds used.

The compounds of the above formula (VI) wherein X is S can be preparedby reacting the compound of the formula (VII) or (VIII):

wherein n; B₁, B₂, . . . , B_(n-1) and B_(n); B′₁, B′₂, . . . , B′_(n-1)and B′_(n); R, <substituent group α>, <substituent group β₁>,<substituent group β2>and <substituent group γ>, PG₁, PG₂ and PG₃ eachhave the same meaning as defined above; and W is a leaving group such asmethanesulfonyloxy, with a base such as sodium hydroxide, lithiumhydroxide or the like in a solvent such as 1,4-dioxan or the like. Inthis reaction, the reaction temperature is usually room temperature tothe boiling point of the solvent used, preferably 100° C., though it maybe appropriately chosen depending on the starting material or thereaction solvent used. Further, the reaction is usually completed within1 to 24 hours, but the reaction time may be appropriately adjusted tomake it longer or shorter.

The compound of the above formula (VII) can be prepared by reacting thecompound of the formula (IX):

-   -   wherein R, <substituent group α>, <substituent group β₁>,        <substituent group β₂>, <substituent group γ>, PG₁ and PG₂ each        have the same meaning as defined above, with a base such as        lithium hexamethyldisilazide or the like in a solvent such as        tetrahydrofuran or the like. In this reaction, the reaction        temperature is usually 0° C. to the boiling point of the solvent        used, preferably room temperature, though it maybe appropriately        chosen depending on the starting material or the reaction        solvent to be used. Further, the reaction is usually completed        within 1 to 24 hours, preferably for 1 hour, but the reaction        time may be appropriately adjusted to make it longer or shorter.

The compound of the above formula (IX) can be prepared from the compoundof the formula (X):

wherein R₁ is lower alkyl such as methyl, ethyl or the like; R,<substituent group α>, <substituent group β₁>, <substituent group β₂>,<substituent group γ> and PG₂ each have the same meaning as definedabove, and 2-cyanoethylamine, according to a method similar to thePreparation Method B-1 described in WO 02/02550.

The compound of the above formula (X) can be prepared from the compoundof the formula (XI):

wherein R₁ and R₂ are the same or different and are each lower alkylsuch as methyl, ethyl or the like, according to a method similar to thePreparation Method A described in WO 02/02550.

The compound of the above formula (XI) can be prepared by reacting acorresponding (2-fluoro-3-iodophenyl)oxoacetic acid ester with carbonmonoxide in a mixed solvent of a solvent such as N,N-dimethylacetamide,N-methylpyrrolidone, N,N-dimethylformamide or the like, and an alcoholsuch as methanol, ethanol or the like, in the presence of a ligand suchas 1,1′-bis (diphenylphosphino)ferrocene or the like, a palladiumcatalyst such as palladium(II) acetate or the like, and a base such astriethylamine or the like. In this reaction, the reaction temperature isusually 50° C. to the boiling point of the solvent to be used, though itmay be appropriately chosen depending on the starting material or thereaction solvent to be used. Further, the reaction is usually completedwithin 1 to 24 hours, but the reaction time may be appropriatelyadjusted to make it longer or shorter.

In addition to the aforementioned method, the compound of the aboveformula (VI) wherein X is S can be prepared from the compound of theabove formula (X) and the compound of the below formula (XII):

wherein n; B₁, B₂, . . . , B_(n-1) and B_(n); B′₁, B′₂, . . . , B′_(n-1)and B′_(n); <substituent group α>, <substituent group β₁>, <substituentgroup β₂>, <substituent group γ> and PG₃ each have the same meaning asdefined above, according to a method similar to the Preparation MethodB-1 described in WO 02/02550.

The compound of the above formula (VI) wherein X is NH can be preparedfrom the compound of the above formula (X) and the compound of the belowformula (XIII):

wherein n; B₁, B₂, . . . , B_(n-1) and B_(n); B′₁, B′₂, . . . , B′_(n-1)and B′_(n); <substituent group α>, <substituent group β₁>, <substituentgroup β₂>, <substituent group γ> and PG₃ each have the same meaning asdefined above; and PG₄ is t-butoxycarbonyl, benzyloxycarbonyl,allyloxycarbonyl, formyl, acetyl, trifluoroacetyl or the like,preferably t-butoxycarbonyl, allyloxycarbonyl or the like, according toa method similar to the Preparation Method B-2b described in WO02/02550.

The compound of the above formula (VI) wherein X is 0 can be preparedfrom the compound of the above formula (X) and the compound of the belowformula (XIV):

wherein n; B₁, B₂, . . . , B_(n-1) and B_(n); B′₁, B′₂, . . . , B′_(n-1)and B′_(n); <substituent group α>, <substituent group β₁>, <substituentgroup β₂>, <substituent group γ> and PG₃ each have the same meaning asdefined above, according to a method similar to the Preparation MethodB-3 described in WO 02/02550.

The compound of the above formula (V) wherein X is S can be preparedfrom the compound of the below formula (XV):

-   -   wherein n; B₁, B₂, . . . , B_(n-1) and B_(n); B′₁, B′₂, . . . ,        B′_(n-1) and B′_(n); R, <substituent group α>, <substituent        group β₁>, <substituent group β₂>, <substituent group γ>, PG₁,        PG₂ and PG₃ each have the same meaning as defined above,        according to a method similar to the Preparation Method B-1        described in WO 02/02550.

The compound of the above formula (XV) can be prepared from the compoundof the below formula (XVI):

-   -   wherein n; B₁, B₂, . . . , B_(n-1) and B_(n); B′₁, B′₂, . . . ,        B′_(n-1) and B′_(n); R, <substituent group α>, <substituent        group β₁>, <substituent group β₂>, <substituent group γ>, PG₁,        PG₂ and PG₃ each have the same meaning as defined above,        according to the Preparation Method B-1 described in WO        02/02550. Alternatively, the compound of the above formula (XV)        can be prepared by an improved version of the Preparation Method        B-1 described in WO 02/02550. That is, the compound of the above        formula (XV) can also be prepared by reacting the compound of        the above formula (XVI) with sulfuryl chloride in a solvent such        as methylene chloride or the like in the presence of an organic        base such as N-methylpyrrolidine, triethylamine or the like. In        this reaction, the reaction temperature is usually −78° C. to        −50° C., though it may be appropriately chosen depending on the        starting material or the reaction solvent to be used. The        reaction is usually completed within 10 to 60 minutes, but the        reaction time maybe appropriately adjusted to make it longer or        shorter.

The compound of the above formula (XVI) can be prepared from thecompound of the below formula (XVII):

-   -   wherein R, <substituent group α>, <substituent group β₁>,        <substituent group β₂>, <substituent group γ>, R₁, PG₁ and PG₂        each have the same meaning as defined above, according to a        method similar to the Preparation Method B-1 described in WO        02/02550.

The compound of the above formula (XVII) can be prepared by reacting thecompound of the below formula (XVIII):

-   -   wherein R, <substituent group α>, <substituent group β₁>,        <substituent group β₂>, <substituent group γ>, R₁ and PG₂ each        have the same meaning as defined above, with an alkali metal        alkoxide such as sodium methoxide or the like in a solvent such        as tetrahydrofuran, methanol or the like. In this reaction, the        reaction temperature is usually room temperature to 50° C.,        preferably room temperature, though it may be appropriately        chosen depending on the starting material or the reaction        solvent to be used. Further, the reaction is usually completed        within 1 to 24 hours, but the reaction time maybe appropriately        adjusted to make it longer or shorter.

The compound of the above formula (XVIII) can be prepared by reactingthe compound of the above formula (X) with thionyl chloride andN,N-dimethylformamide. In this reaction, the reaction temperature isusually room temperature to the boiling point of the solvent to be used,preferably the boiling point, although it may be appropriately chosendepending on the starting material to be used. Further, the reaction isusually completed within 10 to 60 minutes, but the reaction time may beappropriately adjusted to make it longer or shorter.

The compound of the above formula (V) wherein X is NH can be preparedfrom the compound of the below formula (XIX):

wherein n; B₁, B₂, . . . , B_(n-1) and B_(n); B′₁, B′₂, . . . , B′_(n-1)and B′_(n); R, <substituent group α>, <substituent group β₁>,<substituent group β₂>, <substituent group γ>, PG₁, PG₂ and PG₃ eachhave the same meaning as defined above, according to a method similar tothe Preparation Method B-2b described in WO 02/02550.

The compound of the above formula (XIX) can be prepared from thecompound of the above formula (XVII) and the compound of the aboveformula (XIII) according to a method similar to the Preparation MethodB-2b described in WO 02/02550. Alternatively, the compound of the aboveformula (XIX) can also be prepared from the compound of the belowformula (XX):

wherein n; B₁, B₂, . . . B_(n-1) and B_(n); B′₁, B′₂, . . . , B′_(n-1)and B′_(n); R, <substituent group α>, <substituent group β₁>,<substituent group β₂>, <substituent group γ>, PG₁, PG₂ and PG₃ eachhave the same meaning as defined above, with a nucleophile such asdiethylamine, formic acid or the like in a solvent such astetrahydrofuran or the like in the presence of a palladium catalyst suchas tetrakis(triphenylphosphine)palladium(0) or the like. In thisreaction, the reaction temperature is usually 0° C. to room temperature,although it may be appropriately chosen depending on the startingmaterials and the reaction solvent to be used. Further, the reaction isusually completed within 1 to 24 hours, but the reaction time may beappropriately adjusted to make it longer or shorter.

The compound of the above formula (XX) can be prepared from the compoundof the above formula (XVII) and the compound of the above formula (XIII)wherein PG₄ is allyloxycarbonyl, according to a method similar to thePreparation Method B-2b described in WO 02/02550.

Preparation Method B:

The compound of the above formula (II) or (III) wherein Y is an oxygenatom can be prepared by reacting the compound of the below formula (XXI)or (XXII):

wherein X, n; B₁, B₂, . . . , B_(n-1) and B_(n); B′₁, B′₂, . . . ,B′_(n-1) and B′_(n); R, <substituent group α>, <substituent group β₁>,<substituent group β₂>, <substituent group γ> and PG each have the samemeaning as defined above; and W is a leaving group such as a iodineatom, a bromine atom, a methanesulfonyloxy group or the like, with abase such as potassium carbonate or the like in an aprotic polar solventsuch as N,N-dimethylformamide or the like. In this reaction, thereaction temperature is usually room temperature to 100° C., preferably60° C. to 80° C., although it may be appropriately chosen depending onthe starting material and the reaction solvent to be used. Further, thereaction is usually completed within 1 to 24 hours, but the reactiontime may be appropriately adjusted to make it longer or shorter.

The compound of the above formula (XXI) or (XXII) can be preparedaccording to a method similar to the Preparation Method A as mentionedabove.

Preparation Method C:

The compound of the above formula (II) or (III) wherein X is NH and Y isa nitrogen atom can be prepared by reacting the compound of the belowformula (XXIII) or (XXIV) with the compound of the below formula (XXV):

wherein X, n; B₁, B₂, . . . , B_(n-1) and B_(n); B′₁, B′₂, . . . ,B′_(n-1) and B′_(n); R, <substituent group α>, <substituent group β₁>,<substituent group β₂>, <substituent group γ> and PG each have the samemeaning as defined above; and W₁ and W₂ are each independently a leavinggroup such as a iodine atom, a bromine atom, a methanesulfonyloxy groupor the like, in an aprotic polar solvent such as N,N-dimethylformamideor the like. In this reaction, the reaction temperature is usually roomtemperature to the boiling point of the solvent used, preferably 60° C.to 80° C., although it may be appropriately chosen depending on thestarting materials and the reaction solvent to be used. Further, thereaction is usually completed within 10 to 60 minutes, but the reactiontime may be appropriately adjusted to make it longer or shorter.

The compound of the above formula (XXIII) or (XXIV) can be preparedaccording to a method similar to the above Preparation Method A and themethods described in WO 02/02550.

The introduction or conversion of R may be carried out at any one ofsteps in the preparation of the above synthetic intermediates.Hereinafter, such introduction or conversion of R in the compound of theabove formula (II) or (III) is described.

The compound of the above formula (II) or (III) wherein R is methyl canbe prepared from the corresponding compound of the above formula (II) or(III) wherein R is hydroxymethyl. That is, the compound of the aboveformula (II) or (III) wherein R is methyl can be prepared by convertingsaid hydroxymethyl group into methanesulfonyloxymethyl group,chloromethyl group or the like, followed by catalytic hydrogenationusing a transition metal catalyst. Also, the compound of the aboveformula (II) or (III) wherein R is methanesulfonyloxymethyl is reactedin a solvent such as tetrahydrofuran, methanol, 1,4-dioxane or the like,or a mixed solvent thereof in the presence of a transition metalcatalyst such as 10% palladium-carbon catalyst or the like under ahydrogen atmosphere, thereby to produce the compound of the aboveformula (II) or (III) wherein R is methyl. In this reaction, thereaction temperature is usually 0° C. to the boiling point of thesolvent used, although it may be appropriately chosen depending on thestarting material and the solvent to be used in the reaction. Further,the reaction is usually completed within 1 to 24 hours, but the reactiontime may be appropriately adjusted to make it longer or shorter.

Also, the compound of the above formula (II) or (III) wherein R is vinylcan be prepared from the corresponding compound of the above formula(II) or (III) wherein R is a bromine atom. For example, the compound ofthe above formula (II) or (III) wherein R is a bromine atom is reactedwith tributylvinyltin in a solvent such as toluene, 1,4-dioxane,N,N-dimethylformamide or the like, preferably toluene, in the presenceof a palladium catalyst such as tetrakis(triphenylphosphine)palladium(0)or the like, thereby to produce the compound of the above formula (II)or (III) wherein R is vinyl. In this reaction, the reaction temperatureis usually room temperature to the boiling point of the solvent used,preferably 80° C. to 100° C., although it may be appropriately chosendepending on the starting material and the reaction solvent to be used.Further, the reaction is usually completed within 1 to 24 hours, but thereaction time may be appropriately adjusted to make it longer orshorter.

The compound of the above formula (II) or (III) wherein R isN-alkyl-lower alkanoylamino can be prepared from the correspondingcompound of the above formula (II) or (III) wherein R is a bromine atom.For example, the compound of the above formula (II) or (III) wherein Ris a bromine atom is reacted with an amide such as 2-pyrrolidinone orthe like, in a solvent such as toluene, 1,4-dioxane,N,N-dimethylformamide or the like, preferably 1,4-dioxane, in thepresence of a phosphine such as4,5-bis(diphenylphosphino)-9,9-dimethylxanthene or the like, a palladiumcatalyst such as tris(benzylideneacetone)dipalladium(0)-chloroformadduct or the like, and a base such as cesium carbonate or the like,thereby to produce the compound of the above formula (II) or (III)wherein R is N-alkyl-lower alkanoylamino. In this reaction, the reactiontemperature is usually room temperature to the boiling point of thesolvent used, preferably 60° C. to 120° C., though it may beappropriately chosen depending on the starting material and the reactionsolvent to be used. Further, the reaction is usually completed within 1to 24 hours, but the reaction time may be appropriately adjusted to makeit longer or shorter.

The compound of the above formula (II) or (III) wherein R is(dialkyl)aminomethyl or (monoalkyl)aminomethyl can be prepared from thecompound of the above formula (II) or (III) wherein R is hydroxymethyl.That is, the hydroxymethyl of the compound of the above formula (II) or(III) wherein R is (dialkyl)aminomethyl or (monoalkyl)aminomethyl isconverted into the methanesulfonyloxymethyl thereof, the chloromethylthereof or the like, followed by alkylation of the resulting productwith dialkylamine or (monoalkyl)amine, or alkylation of the resultingproduct with dialkylamine in the presence of an acid catalyst.

According to the former method, the compound of the above formula (II)or (III) wherein R is methanesulfonyloxymethyl can be prepared byreacting the compound of the above formula (II) or (III) wherein R ishydroxymethyl, with methanesulfonyl chloride in a solvent such aschloroform, methylene chloride, tetrahydrofuran, N,N-dimethylformamide,diethyl ether, ethyl acetate or the like, in the presence of an organicbase such as triethylamine, diisopropylethylamine or the like. In thisreaction, the reaction temperature is usually 0° C. to room temperature,although it may be appropriately chosen depending on the startingmaterial to be used, and the reaction is usually completed within 1 to 2hours, but the reaction time may be appropriately adjusted to make itlonger or shorter. Further, the compound of the above formula (II) or(III) wherein R is methanesulfonyloxymethyl is reacted with adialkylamine such as piperidine, morpholine, N-methylpiperazine,diethylamine or the like, or (monoalkyl)amine such as cyclopentylamine,t-butylamine or the like in a solvent such as chloroform, methylenechloride, tetrahydrofuran, N,N-dimethylformamide or the like in thepresence of an inorganc base such as potassium carbonate or the like,thereby to produce the compound of the above formula (II) or (III)wherein R is (dialkyl)aminomethyl or (monoalkyl)aminomethyl. In thisreaction, the reaction temperature is usually 0° C. to the boiling pointof the reaction solvent used, although it may be appropriately chosendepending on the starting material and the reaction solvent to be used,and the reaction is usually completed within 1 to 24 hours, but thereaction time may be appropriately adjusted to make it longer orshorter. According to the latter method, the compound of the aboveformula (II) or (III) wherein R is hydroxymethyl is reacted with adialkylamine such as piperidine, morpholine, N-methylpiperazine,diethylamine or the like in a solvent such as chloroform, methylenechloride, tetrahydrofuran, N,N-dimethylformamide, diethyl ether, ethylacetate, toluene or the like in the presence of an acid catalyst such asacetic acid, hydrochloric acid, sulfuric acid, 4-toluenesulfonic acid orthe like, thereby to produce the compound of the above formula (II) or(III) wherein R is (dialkyl)aminomethyl. In this reaction, the reactiontemperature is usually room temperature to the boiling point of thesolvent used for the reaction, although it may be appropriately chosendepending on the starting material and the reaction solvent to be used,and the reaction is usually completed within 1 to 3 days, but thereaction time may be appropriately adjusted to make it longer orshorter.

Further, the compound of the above formula (II) or (III) wherein R is2-[(dialkyl) amino] ethyl can be prepared by addition reaction of thedialkylamino to the corresponding compound of the above formula (II) or(III) wherein R is vinyl, and the production is mentioned above. Forexample, the compound of the above formula (II) or (III) wherein R isvinyl is reacted in a sealed tube using a dialkylamine such aspyrrolidine or the like as a solvent usually at 100° C. to 150° C.,preferably 120° C., although the reaction temperature may beappropriately chosen depending on the starting material and the reactionsolvent to be used, thereby to produce the compound of the above formula(II) or (III) wherein R is 2-[(dialkyl)amino]ethyl. The reaction iscompleted within 1 to 24 hours, but the reaction time may beappropriately adjusted to make it longer or shorter.

Also, the compound of the above formula (II) or (III) wherein R isalkoxycarbonyl can be prepared from the corresponding compound of theabove formula (II) or (III) wherein R is a bromine atom. For example,the compound of the above formula (II) or (III) wherein R is a bromineatom is reacted with carbon monooxide in a solvent including a mixtureof a solvent such as N,N-dimethylacetamide, N-methylpyrrolidone,N,N-dimethylacetamide or the like, and an alcohol such as methanol,ethanol or the like, in the presence of a ligand such as1,1′-bis(diphenylphosphino)ferrocene or the like, a palladium catalystsuch as palladium(II) acetate or the like, and a base such as sodiumhydrogencarbonate or the like, thereby to produce the compound of theabove formula (II) or (III) wherein R is an alkoxycarbonyl group. Inthis reaction, the reaction temperature is usually 50° C. to the boilingpoint of the solvent used in the reaction, though it may beappropriately chosen depending on the starting material and the reactionsolvent to be used, and the reaction is usually completed within 1 to 24hours, but the reaction time may be appropriately adjusted to make itlonger or shorter.

The compound of the above formula (II) or (III) wherein R is amino canbe prepared from the compound of the above formula (II) or (III) whereinR is a bromine atom. For example, the compound of the above formula (II)or (III) wherein R is a bromine atom is reacted with a dialkylamine suchas N-methylpiperazine, piperidine, morpholine or the like in a solventsuch as toluene, 1,4-dioxane, N,N-dimethylformamide or the like,preferably toluene, in the presence of a palladium catalyst such astris(benzylideneacetone)dipalladium-chloroform adduct or the like, aphosphine such as (R)-(+)-2,2′-bis(di-4-tolylphosphino)-1,1′-binaphthylor the like and a base such as sodium t-butoxide or the like, thereby topropduce the compound of the above formula (II) or (III) wherein R is adialkylamino group. In this reaction, the reaction temperature isusually room temperature to the boiling point of the solvent used in thereaction, preferably 60° C. to 120° C., though it may be appropriatelychosen depending on the starting material and the reaction solvent to beused, and the reaction is usually completed within 1 to 24 hours, butthe reaction time may be appropriately adjusted to make it longer orshorter.

The compound of the above formula (II) or (III) wherein R ishydroxycarbonyl can be prepared by reacting the corresponding compoundof the above formula (II) or (III) wherein R is alkoxycarbonyl, with anaqueous solution of sodium hydroxide, potassium hydroxide, lithiumhydroxide or the like in a solvent such as tetrahydrofuran, 1,4-dioxane,methanol, ethanol or the like. In this reaction, the reactiontemperature is usually 0° C. to the boiling point of the solvent used inthe reaction, preferably room temperature, though it may beappropriately chosen depending on the starting material and the reactionsolvent to be used, and the reaction is usually completed within 1 to 24hours, but the reaction time may be appropriately adjusted to make itlonger or shorter.

Further, the compound of the above formula (II) or (III) wherein R ishydroxymethyl can be prepared by reducing the corresponding compound ofthe above formula (II) or (III) wherein R is hydroxycarbonyl. Forexample, the compound of the above formula (II) or (III) wherein R ishydroxycarbonyl is reacted with a condensing agent such asbenzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate or thelike in a solvent such as tetrahydrofuran or the like in the presence ofan organic base such as N,N-diisopropylethylamine or the like at 0° C.to room temperature for 5 minutes to 1 hour, followed by reaction with areducing agent such as lithium tetrahydroborate or the like, thereby toproduce the compound of the above formula (II) or (III) wherein R ishydroxymethyl. In this reaction, the reaction temperature is usually 0°C. to room temperature, though it may be appropriately chosen dependingon the starting material and the reaction solvent to be used, and thereaction is usually completed within 10 minutes to 24 hours, but thereaction time may be appropriately adjusted to make it longer orshorter.

In addition, the compound of the above formula (II) or (III) wherein Ris alkoxymethyl can be prepared by alkylation of the correspondingcompound of the above formula (II) or (III) wherein R is hydroxymethyl.For example, the compound of the above formula (II) or (III) wherein Ris hydroxymethyl is reacted with an alkylating agent such as methyliodide, dimethyl sulfate or the like in a solvent such asN,N-dimethylformamide, 1,4-dioxane, tetrahydrofuran or the like in thepresence of an inorganic base such as sodium hydride, potassium,t-butoxide or the like, thereby to produce the compound of the aboveformula (II) or (III) wherein R is alkoxymethyl. In this reaction, thereaction temperature is usually 0° C. to the boiling point of thesolvent used in the reaction, preferably room temperature, though it maybe appropriately chosen depending on the starting material and thereaction solvent to be used, and the reaction is usually completedwithin 1 to 24 hours, but the reaction time may be appropriatelyadjusted to make it longer or shorter.

The compound of the above formula (II) or (III) wherein R is an aromaticcyclic group or an aromatic heterocyclic group attached via the carbonatom to the quinoxalinone core structure can be prepared from thecorresponding compound of the above formula (II) or (III) wherein R is abromine atom. For example, the compound of the above formula (II) or(III) wherein R is a bromine atom is reacted with a boronic acid such aspyrimidine-5-boronic acid or the like in a solvent such as1,2-dimethoxyethane-water, toluene-water, 1,4-dioxane-water,N,N-dimethylamide or the like in the presence of a palladium catalystsuch as tetrakis(triphenylphosphine)palladium or the like, and a basesuch as potassium carbonate or the like, thereby to produce the compoundof the above formula (II) or (III) wherein R is an aromatic cyclic groupor an aromatic heterocyclic groups attached via the carbon atom to thequinoxalinone core structure. In this reaction, the reaction temperatureis usually room temperature to the boiling point of the solvent used inthe reaction, preferably 60° C. to 120° C., though it maybeappropriately chosen depending on the starting material and the reactionsolvent to be used, and the reaction is usually completed within 1 to 24hours, but the reaction time may be appropriately adjusted to make itlonger or shorter.

The compound of the above formula (II) or (III) wherein R is an aromaticheterocyclic group attached via the nitrogen atom to the quinoxalinonecore structure can be prepared from the corresponding compound of theabove formula (II) or (III) wherein R is a bromine atom. For example,the compound of the above formula (II) or (III) wherein R is a bromineatom is reacted with an aromatic heterocyclic compound such as indole orthe like in a solvent such as toluene, 1,4-dioxane,N,N-dimethylformamide or the like, preferably 1,4-dioxane, in thepresence of a phosphine such as4,5-bis(diphenylphosphino)-9,9-dimethylxanthene or the like, a palladiumcatalyst such as tris(benzylideneacetone)dipalladium(0)-chloroformadduct or the like and a base such as cesium carbonate or the like,thereby to produce the compound of the above formula (II) or (III)wherein R is an aromatic heterocyclic group attached via the nitrogenatom to the quinoxalinone core structure. In this reaction, the reactiontemperature is usually room temperature to the boiling point of thesolvent used in the reaction, preferably 60° C. to 120° C., though itmay be appropriately chosen depending on the starting material and thereaction solvent to be used, and the reaction is usually completedwithin 1 to 24 hours, but the reaction time may be appropriatelyadjusted to make it longer or shorter.

Further, the compounds having other groups represented by R, such aslower alkyl such as ethyl or the like; lower alkyl substituted byaliphatic heterocyclic group; and aliphatic heterocyclic group bondedvia the nitrogen atom to the quinoxaline core structure, may be preparedaccording to the aforementioned methods.

The starting materials, reagents, (2-fluoro-3-iodophenyl)oxoacetic acidester, and the compounds of the above formulae (VIII), (XII), (XIII),(XIV) and (XXV) used in the preparation of the compounds of the formula(I) are all known, or they can be prepared by the per se known methodutilizing the known compounds.

Hereinafter, (2-fluoro-3-iodophenyl)oxoacetic acid ester, and thecompounds of the above formulae (VIII), (XII), (XIII), (XIV) and (XXV)are described.

The (2-fluoro-3-iodophenyl)oxoacetic acid ester can be prepared byreacting a commercially available 2-fluoro-1-iodobenzene with a strongbase such as lithium diisopropylamide, or the like in an ether solventsuch as tetrahydrofuran or the like at a low temperature and thenreacting the resultant lithio compound with a chlorooxoacetatederivative or an oxalic acid diester.

The compound of the above formula (VIII) can be prepared from the diolcompound of the following formula (XXVI):

-   -   wherein n; B₁, B₂, . . . , B_(n-1) and B_(n); B′₁, B′₂, . . . ,        B′_(n-1) and B′_(n); <substituent group α>, <substituent group        β₁>, <substituent group β2> and <substituent group γ> each have        the same meaning as defined above, and the diol compound is        commercially available or can be prepared from the known        compounds such as corresponding diesters, dicarboxylic acids or        the like by the known method such as reduction with lithium        aluminum hydride. That is, the compound of the above        formula (VIII) can be prepared by introducing a protecting group        into one of the hydroxy groups in the diol compound of the above        formula (XXVI) to convert into the compound of the formula        (XXVII):    -   wherein n; B₁, B₂, . . . , B_(n-1) and B_(n); B′₁, B′₂, . . . ,        B′_(n-1) and B′_(n); <substituent group α>, <substituent group        β₁>, <substituent group β₂>, <substituent group γ>and PG₃ each        have the same meaning as defined above, and then reacting the        other hydroxy group with methanesulfonyl chloride or the like in        the presence of a base such as triethylamine or the like.

The aminoalcohol derivative of the above formula (XII) is commerciallyavailable, or can be prepared by introducing a protecting group into thehydroxy group of the commercially available aminoalcohol. Alternatively,the aminoalcohol derivative of the above formula (XII) can be preparedby substituting the leaving group W of the compound of the above formula(VIII) with-an azido group using sodium azide or the like in a polarsolvent such as dimethylformamide or the like and then subjecting theresulting product to catalytic hydrogenation using a palladium catalyst,thereby to reduce the azide group into the amino group.

The hydrazine derivative of the above formula (XIII) can be prepared byoxidizing a commercially available aldehyde or ketone or the hydroxygroup of the compound of the above formula (XXVII) with a sulfurtrioxide-pyridine complex and then obtaining the objective compound fromthe resultant aldehyde or ketone. That is, the carbonyl group of thesecompounds is converted into the hydrazide group, and then the resultantcompound is reacted with a reducing agent such as sodiumtetrahydroborate, sodium cyanotrihydroborate, sodiumtriacetoxyhydroborate or the like in the presence of an acid such asacetic acid, trifluoroacetic acid, hydrochloric acid, 4-toluenesulfonicacid, zinc chloride or the like, thereby to give the compound of theabove formula (XIII).

The hydroxylamine derivatives of the above formula (XIV) can be preparedby introducing a protecting group into the two hydroxy groups of ahydroxylamine obtained by the reduction of a commercially availableoxime according to a method similar to the aforementioned method.

The dihalogenated alkyl derivative or disulfonic acid ester derivativeof the above formula (XXV) is commercially available, or can be preparedby converting the two hydroxy groups of the compound of the aboveformula (XXVI) into the disulfonic acid ester with methanesulfonylchloride or the like. Further, the disulfonic acid ester is reacted withsodium iodide in a polar solvent such as dimethylformamide or the liketo produce the corresponding dihalogenated alkyl derivative.

With respect to the novel quinoxalinone compounds prepared by the abovemethods, Cdk inhibitory activity (cyclin D2-Cdk4 inhibitory activity andcyclin D2-Cdk6 inhibitory activity are described as examples) andinhibitory activity of 5-bromo-2′-deoxyuridine:BrdU) uptake are shownbelow.

Cdk4 Inhibitory Activities

(1) Purification of Cyclin D2-Cdk4

cDNAs of Cdk4 and its activating factor cyclin D2 were each introducedinto a baculovirus expression vector to obtain a recombinantbaculovirus; it was then co-infected to an insect cell Sf9 to highlyexpress active cyclin D2/Cdk4 complexes. The cells were recovered,solubilized and the enzymes were purified by HPLC column chromatography(The Embo Journal, vol. 15, 7060-7069 (1996)).

(2) Determination of Cyclin D2-Cdk4 Activity

In the determination of cyclin D2-Cdk4 activity, a synthetic peptideArg-Pro-Pro-Thr-Leu-Ser-Pro-Ile-Pro-His-Ile-Pro-Arg corresponding to theamino acid number 775-787 of RB protein was used as a substrate [TheEMBO Journal, vol. 15, 7060-7069 (1996)].

The reaction was carried out according to a method partially modifyingKitagawa et al. (Oncogene, vol. 7, 1067-1074 (1992)). Purified cyclinD2-Cdk4, 100 μM substrate peptide, 50 μM non-labeled adenosinetriphosphate (ATP) and 1 μCi [γ-33P]-labeled ATP (2000-4000 Ci/mmole)were added to a reaction buffer (referred to as R buffer) consisting of20 mM Tris-HCl buffer (pH 7.4), 10 mM magnesium chloride, 4.5 mM2-mercaptoethanol and 1 mM ethylene glycol bis(β-aminoethylether)-N,N,N′,N′-tetraacetic acid (EGTA) to make a total volume of 21.1μl. The mixture was incubated at 30° C. for 45 minutes. After that, 350mM phosphate buffer (10 μl) was added to the reaction solution to stopthe reaction. The peptide substrate was adsorbed on a P81 paper filterin a 96-well plate, and the plate was washed several times with 75 mMphosphate buffer, and then its radioactivity was measured by a liquidscintillation counter. The [γ-33P]-labeled ATP was purchased fromDaiichi Pure Chemicals.

Addition of test compounds to the reaction system was carried out insuch a manner that the compounds were dissolved in dimethyl sulfoxide toprepare a series of diluted solutions, and then each aliquot (1.1 μl)was added to the reaction system. A control group was prepared byaddition of only dimethyl sulfoxide (1.1 μl) to the reaction system.

The compounds in the following Working Examples were chosen as typicalcompounds of the present invention, and IC₅₀ values against cyclinD2-Cdk4 activity of those compounds were determined. The results areshown in the table below. TABLE 1 Compound of Working Example (shown bythe number only) IC₅₀(nM) [1] 3.6 [4] 2.5 [5] 4.3 [6] 2.9 [7] 3.5 [8]6.1 [9] 11 [10] 6.3 [11] 12 [12] 11 [14] 2.2 [20] 1.6 [23] 2.1 [25] 8.2[28] 16 [31] 6.4 [32] 9 [34] 12 [35] 12 [36] 34 [37] 17 [38] 12 [39] 6.9[45] 14 [46] 3.1 [48] 3.6 [51] 6.1 [54] 8.5 [55] 7.9 [56] 9.2 [65] 6.9[71] 13 [80] 1.7 [83] 2 [84] 6.2 [85] 6.7 [86] 2.7 [87] 2.6 [89] 2.7[90] 3.7 [91] 3.2 [92] 2.8 [94] 3.6 [95] 4.1 [99] 5.2 [100] 2.4 [102]1.4 [104] 1.6 [107] 7.7 [111] 5.5 [118] 14 [122] 2.5 [123] 9.6 [124] 8.2[125] 15 [126] 9.4 [127] 11 [128] 3.5 [129] 4.9 [130] 6.5 [131] 8.2[134] 6.4 [135] 2.5 [136] 3.2 [137] 3.4 [138] 4.2 [139] 3 [140] 3 [141]26 [142] 15 [143] 2.2 [144] 2.9 [145] 2.7 [146] 5.2

These results clearly show that the compounds of the present inventionexhibit strong inhibitory activities against cyclin D2-Cdk4.

Cdk6 Inhibitory Activities

(1) Purification of Cyclin D2-Cdk6

In the same manner as with cyclin D2-Cdk4, cDNAs of Cdk6 and itsactivating factor cyclin D2 were each introduced into a baculovirusexpression vector to obtain a recombinant vaculovirus; it was thenco-infected to an insect cell Sf9 to highly express active cyclinD2/Cdk6 complexes. The cells were recovered, solubilized and the enzymeswere purified by a HPLC column chromatography.

(2) Determination of Cyclin D2-Cdk6 Activity

In the determination of cyclin D2-Cdk6 activity, a synthetic peptideArg-Pro-Pro-Thr-Leu-Ser-Pro-Ile-Pro-His-Ile-Pro-Arg was used.

The reaction was carried out according to a method partially modifyingKitagawa et al. (Oncogene, vol. 7, 1067-1074 (1992)). Purified cyclinD2-Cdk6, 100 μM substrate peptide, 50 μM non-labeled ATP and 1.5 μCi[γ-33P]-labeledATP (2000-4000 Ci/mmole) were added to R buffer to make atotal volume of 21.1 μl. The mixture was reacted at 30° C. for 40minutes, and then 350 mM phosphate buffer (10 μl) was added to thereaction solution to stop the reaction. The peptide substrate wasadsorbed on a P81 paper in a 96-well plate, and the plate was washedwith 75 mM phosphate buffer, and then its radioactivity was measured bya liquid scintillation counter.

Addition of test compounds to the reaction system was carried out insuch a manner that the compounds were dissolved in DMSO to prepare aseries of diluted solutions, and then each aliquot (1.1 μl) was added tothe reaction system. A control group was prepared by addition of onlydimethyl sulfoxide (1.1 μl) to the reaction system.

The compounds of [11], [51] and [134] were chosen as typical compoundsof the present invention, and IC₅₀ values against cyclin D2-Cdk6activity of those compounds were determined. The results are shown inthe table below. TABLE 2 Compound of Working Example (shown by thenumber only) IC₅₀(nM) [11] 24 [51] 25 [134] 12

These results clearly show that the compounds of the present inventionexhibit strong inhibitory activities against cyclin D2-Cdk6.

As mentioned above, since the compounds of the present invention havestrong Cdk inhibitory activities, they are useful as a Cdk inhibitoryagent. Further, the Cdk inhibitory agent may contain a pharmaceuticallyacceptable carrier or diluent.

Inhibitory Activities of 5-bromo-2′-deoxyuridinee (BrdU) Uptake

Growing cells perform DNA duplication in the S phase of the cell cycle,and divide into daughter cells in the M phase via the G2 phase. As anindex for the cell growth, there is a method to determine the amount ofBrdU taken into newly synthesized DNAs in the DNA duplicating cells ((J.Immunol Methods, vol. 82, p. 169-179 (1985); J. Immunolog. Methods, vol.106, p. 95-100 (1988); Cytometry, vol. 14, p. 640-648 (1993)).Inhibitory activities of BrdU uptake was determined in order toinvestigate the effect of the compounds of the present invention againstcancer cells.

(1) Method for Cell Culture

HCT116 cells derived from human colon cancer were cultured in Dulbecco'smodified Eagle's medium containing 10% fetal bovine serum at 37° C. inthe presence of 5% carbon dioxide under an atmosphere of saturatedsteam.

(2) Determination of Inhibitory Activities of BrdU Uptake

Cell culture medium (100 μl each) containing 2.5×10³ of HCT116 cells wasdispensed into each well of a 96-well cell culture dish, and then thecells were pre-cultured overnight. On the next day, a series of dilutedsolutions was prepared with DMSO from a DMSO solution containing thecompounds of the present invention. Then, a series of diluted solutions,or DMSO only as a control without addition of the compound, was added inan amount of 1% to the cell culture medium. Finally, 100 μl of culturemedium containing the above diluted solution containing the compounds orDMSO only were each added to the cells which had been pre-cultured inthe 96-well dish, and then the cells were cultured for 12 hours.

Quantitative determination of BrdU uptake was performed using the CellProliferation ELISA, BrdU (chemiluminescence)(Roche Diagnostics). Each20 μL of 10× concentrated BrdU labeling reagent was added to the cellswhich had been cultured together with the compound for 12 hours, whichwere subjected to pulse labeling at 37° C. for 1 hour, and then theculture solution was removed. Then, after addition of a FixDenatsolution to the cells, the cells were incubated at room temperature for30 minutes for fixation of cells and denaturation of DNA. After removalof the FixDenat solution, anti-BrdU antibody labeled with peroxidase wasadded to the cells, and then the cells were incubated at roomtemperature for 90 minutes. The cells were washed four times with awashing solution, and a substrate was added thereto. The cells wereincubated at room temperature for 10 minutes and chemical luminescencewas determined with a luminometer.

As typical compounds of the present invention, the compounds [11], [12],[39], [51], [71], [83], [85], [134] and [141] were chosen, and IC50values of these compounds on BrdU uptake were determined. The resultsare shown in table 3. TABLE 3 Compounds of Working Examples (hereinaftershown by the number only) IC₅₀(nM) [11] 16 [12] 9.7 [39] 9.4 [51] 23[71] 75 [83] 30 [85] 20 [134]  7.8 [141]  20

The compounds of the present invention are useful as anti-cancer agents(cancer remedies) for treatment of cancers, because they stronglyinhibit BrdU uptake and thus apparently have cell growth-inhibitoryactivity. That is, a pharmaceutical composition containing a novelquinoxalinone derivative or a pharmaceutically acceptable salt or esterthereof according to the present invention, or an anti-cancer agentcontaining a novel quinoxalinone derivative or a pharmaceuticallyacceptable salt or ester thereof according to the present invention areeffective for the treatment of cancer patients. Also, saidpharmaceutical composition and anti-cancer agent may contain apharmaceutically acceptable carrier or diluent. In the abovedescription, “pharmaceutically acceptable carrier or diluent” meansexcipients (e.g. fat, bees wax, semi-solid or liquid polyol, natural orhydrogenated (hardened) oil); water (e.g. distilled water, especiallydistilled water for injection); physiological saline, alcohols (e.g.ethanol), glycerol, polyol, aqueous glucose, mannitol, vegetable oil orthe like; and additives (e.g. fillers, disintegrating agents, binders,lubricants, wetting agents, stabilizers, emulsifiers, dispersing agents,preservatives, sweeteners, pigments, condiments or perfumes, thickeningagents, diluting agents, buffers, solvents or solubilizers, agents forattaining storage effect, salts for adjusting osmotic pressure, coatingagents or anti-oxidants).

Suitable tumors against which the compounds of the present invention areexpected to exhibit a therapeutic effect are, for example, human solidcancers. Examples of the human solid cancers are brain cancer, head andneck cancer, esophagus cancer, thyroid cancer, small cell cancer,non-small cell cancer, breast cancer, stomach cancer, gallbladder/bileduct cancer, hepatic cancer, pancreatic cancer, colon cancer, rectalcancer, ovarian cancer, chorioepithelioma, uterine cancer, cervicalcancer, renal pelvic/ureteral cancer, bladder cancer, prostate cancer,penile cancer, testicular cancer, embryonal cancer, Wilms cancer, skincancer, malignant melanoma, neuroblastoma, osteosarcoma, Ewing's sarcomaand soft tissue sarcoma.

The aforementioned “a pharmaceutically acceptable salt or ester” isdescribed below.

When the compounds of the present invention are used as an anti-canceragent, they may be used as a pharmaceutically acceptable salt thereof.Typical examples of such pharmaceutically acceptable salt are a saltwith an alkali metal such as sodium, potassium or the like,hydrochloride, and trifluoroacetate.

A pharmaceutically, if desired, acceptable salt of the present inventionmay be prepared by combination of conventional methods employed in thefield of synthetic organic chemistry. A specific example includesneutralization of a free-form solution of the compounds of the presentinvention with an alkali solution or an acidic solution.

The esters of the compounds of the present invention include, forexample, methyl ester and ethyl ester. These esters can be prepared byesterification of a free carboxyl group of the compounds according to aconventional method.

The dosage form of the compounds of the present invention can be chosenfrom a variety of forms, and include, for example, oral formulationssuch as tablets, capsules, powders, granules, solution or the like, andsterilized liquid parenteral formulations such as solutions, suspensionsor the like.

Here, the solid pharmaceutical preparations may be manufactured astablets, capsules, granules or powders, with or without a suitableadditive according to a conventional method. Such additive includes, forexample, sugars such as lactose and glucose; starches such as cornstarch, wheat., and rice; fatty acids such as stearic acid; inorganicsalts such as sodium metasilicate, magnesium aluminate, and anhydrouscalcium phosphate; synthetic polymers such as polyvinylpyrrolidone, andpolyalkylene glycol; fatty acid salts such as calcium stearate, andmagnesium stearate; alcohols such as stearyl alcohol, and benzylalcohol; synthetic cellulose derivatives such as methylcellose,carboxymethyl cellulose, ethyl cellulose, and hydroxypropylmethylcellulose; and other additives commonly used such as water, gelatin,talc, vegetable oil, gum arabic or the like.

These solid preparations such as tablets, capsules, granules or powdersmay generally contain 0.1 to 100%, preferably 5 to 100%, more preferably5 to 85%, particularly preferably 5 to 30%, by weight, of an activeingredient.

The liquid preparations such as suspensions, syrups or injections can beprepared by using a suitable additive (e.g. water, alcohols, orplant-derived oils such as soy bean oil, peanut oil or sesame oil)commonly used for the preparation of liquid preparations.

Especially, examples of suitable solutions or diluents for parenteraladministration such as intramuscular, intravenous, or subcutaneousinjection are distilled water for injection, aqueous solution oflidocaine hydrochloride (for intramuscular injection), physiologicalsaline, aqueous glucose solution, ethanol, intravenous injectionsolutions (e.g. aqueous solutions of citric acid or sodium citrate),electrolytic solutions (e.g. intravenous drip infusion, intravenousinjection) and a mixed solution thereof.

Further, these injection preparations can be in a previously-dissolvedform as well as a powder itself with or without additives which are tobe dissolved when used. These injection solutions usually may contain0.1 to 10%, preferably 1 to 5%, by weight, of an active ingredient.

The preferred practical dosage of the compounds of the present inventionmay be properly determined depending on the kind of compounds to beused, the kind of compositions to be combined, administration frequency,a specific part of human body to be treated, and the conditions ofpatients. For example, a daily dose per adult is: in the case of oraladministration, 10 to 500 mg, preferably 10 to 200 mg; in the case ofparenteral administration, preferably intravenous injection, 10 to 100mg, preferably 10 to 30 mg. Although administration frequency variesdepending on the administration route and the diseases of patients, itcan be administered in single or two to five divisions, preferably twoto three divisions.

EXAMPLES

The present invention will be described in more detail in conjunctionwith Working Examples hereinafter, but it is to be construed that thepresent invention is not limited thereto.

For example, when a racemate is described in Working Examples, chiralcompounds thereof should be included in the present invention. Also,preparation methods of the compounds represented by the formulae [A-1]to [A-34] are described in Reference Examples 1 to 34.

Thin-layer chromatography in Working Examples and Reference Examples wascarried out using silica gel ₆₀F₂₅₄ (Merck) as a plate and a UV detectoras a detection method. Wakogel™C-300 or C-200 (Wako Pure ChemicalIndustries, Ltd.) or NH (Fuji Silysia Chemical) was used as silica gelfor the column chromatography. Mass spectrum was measured by use ofJMS-SX102A (JEOL Ltd.) or QUATTROII (Micromass Ltd.). Determination ofNMR spectrum by use of deutero dimethyl sulfoxide was carried out withGemini-200 spectrometer (200 MHz; Varian Inc.), Gemini-300 spectrometer(300 MHz; Varian Inc.) or VXR-300 spectrometer (300 MHz; Varian Inc.),respectively using dimethyl sulfoxide as an internal standard. All δvalues were expressed in terms of ppm.

The abbreviations used in the determination of NMR spectrum are asfollows:

-   -   s: singlet    -   d: doublet    -   dd: double doublet    -   t: triplet    -   dt: double triplet    -   q: quartet    -   m: multiplet    -   br: broad    -   J: coupling constant    -   Hz: herz    -   DMSO-d₆: deutero dimethyl sulfoxide

The abbreviations used in Working Examples and Reference Examples are asfollows:

-   -   TBS: t-butyldimethylsilyl    -   Ms: methanesulfonyl    -   Bz: benzoyl    -   TBDPS: t-butyldiphenylsilyl    -   Alloc: allyloxycarbonyl    -   Ac: acetyl    -   DMTrt: 4,4′-dimethoxytrityl    -   Boc: t-butoxycarbonyl    -   SEM: 2-(trimethylsilyl)ethoxymethyl    -   Bn: benzyl    -   MOM: methoxymethyl    -   Me: methyl    -   Et: ethyl

Working Example 1

Synthesis of the Compound of the Following Formula [1]:

The methyl ester derivative (9.90 g, 17.2 mmol) of the followingformula:

prepared by referring to the procedure of Working Example 110-2)described in WO 02/02550, and benzyl mercaptan (2.63 mL, 22.4 mmol) weredissolved in tetrahydrofuran (100 mL), and to this solution 1Mtetrahydrofuran solution (22.4 mL) in which lithium hexamethyldisilazidewas dissolved at room temperature, was gradually added. The reactionsolution was stirred at the same temperature for 30 minutes, and then 1Naqueous sodium hydroxide (100 mL) and methanol (100 mL) were addedthereto; the reaction solution was stirred at 60° C. for 150 minutes.After the reaction solution was cooled down to 0° C., it was neutralizedusing 1N hydrochloric acid. Saturated aqueous ammonium chloride wasadded to the reaction solution and it was subjected to extraction withchloroform. The organic layer was dried over anhydrous magnesiumsulfate, filtered, and concentrated. The resulting residue was purifiedby a column chromatography on silica gel to obtain the above carboxylicacid derivative (11.4 g) as a pale yellow solid.

Triethylamine (79 μL, 561 μmol) and 5-amino-1-pentanol (29 mg, 281 μmol)were added to a chloroform solution (1 mL) containing the carboxylicacid derivative (100 mg, 151 μmol) prepared in the above (1). Afterthat, a chloroform solution (1 mL) of 2-chloro-1,3-dimethylimidazoliniumchloride (47 mg, 281 μmol) was added dropwise thereto with stirringunder ice-cooling. The mixture was stirred at room temperature for 30minutes, and then concentrated in vacuo. The residue was purified bythin layer chromatography to obtain the above amide derivative (102 mg)as a pale yellow oil.

The above amide derivative (102 mg, 136 μmol) prepared in the above (2)was dissolved in chloroform (2 mL). After the solution was cooled to 0°C., 3-chloroperbenzoic acid (about 80%, 23 mg, 136 μmol) was added. Thereaction solution was stirred at the same temperature for 1 hour, andtriethylamine (114 μL, 816 μmol) and trichloroacetic anhydride (99 μL,544 μmol) were added. Then, the temperature of the reaction solution wasraised to room temperature, and the solution was stirred for 30 minutes,followed by addition of methanol (4 mL). After the reaction solution wasstirred under heating at reflux for 1 hour, and the temperature of thereaction solution was lowered to room temperature. The reaction solutionwas diluted with chloroform, and washed with water and saturated brine.The organic layer was dried over anhydrous magnesium sulfate, filtered,and the filtrate was concentrated. The resulting residue was purified bya thin layer chromatography to obtain the above benzoisothiazolonederivative (80 mg) as a yellow solid.

The benzoisothiazolone derivative (80 mg, 122 μmol) obtained in theabove (3) was dissolved in chloroform (2 mL) and methanol (1 mL), and tothis solution 4N hydrogen chloride/1,4-dioxane (3 mL) was added, andthen the mixture was stirred at room temperature for 3 hours. Theresulting reaction solution was neutralized with aqueous sodiumhydrogencarbonate under ice-cooling, extracted with chloroform, and theorganic layer was washed with saturated brine. Then, the organic layerwas dried over anhydrous magnesium sulfate, filtered, and the filtratewas concentrated. The residue was purified by a thin layerchromatography to obtain the above phenol derivative (52 mg) as a yellowsolid.

To tetrahydrofuran solution (1 nL) containing the phenol derivative (10mg, 19 μmol) obtained in the above (4) were added triphenylphosphine (15mg, 57 μmol) and 40% toluene solution (25 μL) containing diethylazodicarboxylate, and the mixture was stirred at room temperature for 30minutes. The reaction solution was concentrated, and the resultingresidue was purified by a thin layer chromatography to obtain the abovecyclic compound (10 mg) as a yellow solid.

The cyclic compound obtained in the above (5) was dissolved in 4Nhydrogen chloride/1,4-dioxane solution (2 mL), and the solution wasstirred in a sealed tube at 100° C. for 2 hours. Diethyl ether was addedto the reaction solution, and the resulting precipitated solid wasfiltered off to obtain the objective compound [1] (6.3 mg) as a yellowsolid.

Spectral data of the compound of the above formula [1] are shown below.

¹H-NMR(DMSO-d₆)δ:1.80-2.40(6H,m),3.79-3.90(2H,m),4.15-4.30(2H,m),6.81-6.97(2H,m),7.40-7.62(2H,m),7.99(1H,d,J=7.7Hz),9.27(1H,d,J=7.7 Hz),12.8(1H,brs).

mass:380(M+1)⁺

Working Example 2

Synthesis of the Compound of the Following Formula [2]:

According to a method similar to the procedure described in WorkingExample 1, the objective compound [2] (20 mg) which is a racemate wasobtained as a yellow solid from the above carboxylic acid derivative(100 mg, 154 μmol) obtained in Working Example 1-(1) and racemic5-amino-1-hexanol synthesized by referring to the method described in J.Med. Chem., 25(8) 964 (1982).

Spectral data of the compound of the above formula [2] are shown below.

¹H-NMR(DMSO-d₆)δ:1.24(3H,d,J=6.6Hz),1.70-2.05(3H,m),2.20-2.65(3H,m),4.05-4.65(3H,m),6.95-6.98(2H,m),7.51(1H,t,J=8.2Hz), 7.61(1H,t,J=7.7 Hz),8.02(1H,d,J=7.7 Hz),9.42(1H,d,J=8.0Hz),12.8(1H,s).

mass:394(M+1)⁺

Working Example 3

Synthesis of the Compound of the Following Formula [3]:

According to a method similar to the procedures described in WorkingExamples 1-(2) to 1-(3), the above benzoisothiazolone derivative (480mg) was obtained as a yellow solid from the carboxylic acid derivative(1.08 g, 1.46 mmol) obtained in Working Example 1-(1) and2-aminoethanol.

To chloroform solution (1 mL) containing the above benzoisothiazolonederivative (30 mg, 48 μmol) obtained in the above (1) were addedtriphenylphosphine (38 mg, 98 μmol), the sulfonamide derivative [A-3-1](38 mg, 101 μmol) and 40% toluene solution containing diethylazodicarboxylate (43 μL, 98 μmol), and the mixture was stirred at roomtemperature for 4 hours. The resulting solution was purified by thinlayer chromatography to obtain the above benzoisothiazolone (41 mg) as ayellow solid.

According to a method similar to the procedures described in WorkingExamples 1-(4) to 1-(5), the above cyclic derivative (11 mg) wasobtained as a yellow solid from the above benzoisothiazolone derivative(29 mg, 30 μmol).

To N,N-dimethylformamide solution (1 mL) of the cyclic derivative (11mg, 15 μmol) obtained in the above (3) were added thiophenol (19 μL, 18μmol) and sodium carbonate (6 mg, 55 μmol), and the mixture was stirredat room temperature for 15 hours. After addition of water, the resultingreaction solution was extracted with chloroform and the organic layerwas washed with saturated brine. Then, the organic layer was dried overanhydrous magnesium sulfate, filtered and the filtrate was concentrated.The resulting residue was purified by a thin layer, chromatography toobtain the amine derivative (7 mg) as a yellow solid.

According to a method similar to the procedure described in WorkingExample 1-(6), the hydrochloride (2 mg) of the objective compound [3]was obtained as a yellow solid from the amine derivative (3 mg, 5.7μmol) obtained in the above (4).

Spectral data of the compound of the above formula [3] are shown below.

¹H-NMR(DMSO-d₆)δ:1.41(3H,d,J=6.0 Hz)3.20-3.90(4H,m),4.00-4.20(1H,m),4.35-4.50(1H,m),5.05-5.18(1H,m),7.00-7.15(2H,m),7.52-7.78(2H,m),8.15(1H,d,J=7.5Hz),9.42(1H,d,J=7.7 Hz),13.0(1H,s).

mass:395(M+1)⁺.

Example 4

Synthesis of the Compound of the Following Formula [4]:

According to a method similar to the procedures described in WorkingExample 3-(2) to 3-(5), the hydrochloride (2 mg) of the objectivecompound [4] was obtained as a yellow solid from the benzoisothiazolonederivative (15 mg, 24 μmol) obtained in Working Example 3-(1) and thesulfonamide derivative [A-3-2] (19 mg, 51 μmol).

Spectral data of the compound of the above formula [4] are shown below.

¹H-NMR(DMSO-d₆)δ:1.41(3H,d,J=6.0Hz),3.20-3.90(4H,m),4.00-4.20(1H,m),4.35-4.50(1H,m),5.05-5.18(1H,m),7.00-7.15(2H,m),7.52-7.78(2H,m),8.15(1H,d,J=7.5Hz),9.42(1H,d,J=7.7 Hz),13.0(1H,s).

mass:395(M+1)⁺.

Working Example 5

Synthesis of the Compound of the Following Formula [5]:

According to a method similar to the procedures described in WorkingExamples 3-(2) to 3-(5), the hydrochloride (2 mg) of the objectivecompound [5] was obtained as a yellow solid from the benzoisothiazolonederivative (15 mg, 24 μmol) obtained in Working Example 3-(1) and thesulfonamide derivative [A-3-3](19 mg, 51 μmol).

Spectral data of the compound of the above formula [5] are shown below.

¹H-NMR(DMSO-d₆)δ:1.44(3H,d,J=6.2Hz),3.10-4.55(7H,m),7.04-7.13(2H,m),7.58-7.77(2H,m),8.15(1H,d,J=7.7Hz),8.43(1H,brs),9.39(1H,d,J=7.8 Hz),9.98(1H,brs),13.0(1H,s).

mass:395(M+1)⁺.

Working Example 6

Synthesis of the Compound of the Following Formula [6]:

To methanol solution (500 μL) containing the amine derivative (4 mg, 7.6μmol) obtained in Working Example 3-(4) was added 35% aqueous formalinsolution (8 μL), and then methanol solution (500 μL) containing zincchloride (10 mg, 75 μmol) and sodium cyanotrihydroborate (9.4 mg, 150μmol) was added dropwise thereto. The mixture was stirred at roomtemperature for 1 hour. The reaction solution was purified by a thinlayer chromatography to obtain the above N-methyl derivative (4 mg) as ayellow solid.

According to a method similar to the procedure of Working Example 1-(6),the hydrochloride (3 mg) of the objective compound [6] was obtained as ayellow solid from the N-methyl derivative (4 mg, 7.4 μmol) obtained inthe above (1).

Spectral data of the compound of the above formula [6] are shown below.

¹H-NMR(DMSO-d₆)δ:1.41(3H,d,J=6.0 Hz),2.37(3H,s),2.40-4.30(6H,m),4.85-4.98(1H,m),6.90-7.01(2H,m),7.45-7.61(2H,m),8,02(1H,d,J=7.6Hz),9.34(1H,d,J=8.1 Hz),12.7(1H,brs).

mass:409(M+1)⁺.

Working Example 7

Synthesis of the Compound of the Following Formula [7]:

According to a method similar to the procedures of Working Examples3-(2) to 3-(4) and 6, the hydrochloride (3 mg) of the objective compound[7] was obtained as a yellow solid from the benzoisothiazolonederivative (15 mg, 24 μmol) obtained in Working Example 3-(1) and thesulfonamide derivative [A-3-4] (19 mg, 51 μmol).

Spectral data of the compound of the above formula [7] are shown below.

¹H-NMR(DMSO-d₆)δ:0.90-1.40(3H,m),2.20-4.40(10H,m),6.90-7.05(2H,m),7.50-7.70(2H,m),8.00-8.15(1H,m),9.37(1H,d,J=7.9 Hz),12.8(1H,brs).

mass:409(M+1)⁺.

Working Example 8

Synthesis of the Compound of the Following Formula [8]:

According to a method similar to the procedures described in WorkingExamples 3-(2) to 3-(4) and 6, the hydrochloride (2 mg) of the objectivecompound [8] was obtained as a yellow solid from the benzoisothiazolonederivative (15 mg, 24 μmol) obtained in Working Example 3-(1) and thesulfonamide derivative [A-3-3] (19 mg, 51 μmol).

Spectral data of the compound of the above formula [8] are shown below.

¹H-NMR(DMSO-d₆)δ:0.90-1.40(3H,m),2.20-4.40(10H,m) 6.90-7.05(2H,m),7.50-7.70(2H,m),8.00-8.15(1H,m),9.37(1H,d,J=7.9 Hz),12.8(1H,brs).

mass:409(M+1)⁺.

Working Example 9

Synthesis of the Compound of the Following Formula [9]:

According to a method similar to the procedures described in WorkingExample 3-(2) to 3-(4) and 6, the hydrochloride (2 mg) of the objectivecompound [9] was obtained as a yellow solid from the benzoisothiazolonederivative (15 mg, 24 μmol) obtained in Working Example 3-(1) and thesulfonamide derivative [A-3-5] (19 mg, 51 μmol).

Spectral data of the compound of the above formula [9] are shown below.

¹H-NMR(DMSO-d₆)δ:2.30-4.90(11H,m),6.82-7.18(2H,m),7.40-7.80(2H,m),7.95-8.20(1H,m),9.38(1H,d,J=7.8 Hz),12.7-13.1(1H,m).

mass:395(M+1)⁺

Working Example 10

Synthesis of the Compound of the Following Formula [10]:

According to a method similar to the procedures described in WorkingExamples 1-(2) to 1-(3), the above benzoisothiazolone derivative (1.94g) was obtained as a yellow solid from the calboxylic acid derivative(2.00 g, 3.00 mmol) obtained in Working Example 1-(1) andaminoacetaldehyde diethylacetal (873 μL, 6.02 mmol).

To tetrahydrofuran solution (600 mL) of the benzoisothiazolonederivative (1.94 g, 2.82 mmol) obtained in the above (1) was added water(50 mL), and then 4N hydrogen chloride/1,4-dioxane(50 mL) was addedthereto. The mixture was stirred at room temperature for 15 hours. Thereaction solution was concentrated to about 100 mL, and the resultingyellow solid was filtered off. After that, this solid was washed withdiethylether, and dried in vacuo to obtain the above aldehyde derivative(1.01 g) as a yellow solid.

To methanol solution (5 mL) containing the aldehyde derivative (100 mg,207 μmol) obtained in the above (2) was added racemic3-hydroxypyrrolidine (34 μL, 414 μmol), and then methanol solution (2.8mL) containing zinc chloride (56 mg, 414 μmol) and sodiumcyanotrihydroborate (52 mg, 828 μmol) were added dropwise thereto. Themixture was stirred at room temperature for 15 hours, and the reactionsolution was concentrated. The resulting residue was purified by a thinlayer chromatography to obtain the above racemic amine derivative (95mg) as a yellow solid.

According to a method similar to the procedures described in WorkingExamples 1-(5) to 1-(6), the hydrochloride (31 mg) of the objectivecompound [10] as a racemate was obtained as, a yellow solid from theracemic amine derivative (95 mg, 171, μmol) obtained in the above (3).

Spectral data of the compound of the above formula [10] are shown below.

¹H-NMR(DMSO-d₆)δ:1.80-4.00(8H,m),4.00-4.40(2H,m),5.38-5.42(1H,m),6.80-7.30(2H,m),7.40-7.80(2H,m),7.95-8.18(1H,m),9.24-9.36(1H,m),12.7(1H,s).

mass:407(M+1)⁺.

Working Example 11

Synthesis of the Compound of the Following Formula [11]:

To toluene solution (4 mL) containing the keto ester derivative [A-2](515 mg, 2.03 mmol) and the phenylenediamine derivative [A-1] (643 mg,2.03 mmol) was added acetic acid (0.4 mL), and the mixture was stirredat room temperature for 3 days. The resulting precipitates were filteredoff, washed with diethyl ether and toluene, and dried in vacuo to obtainthe above quinoxalinone derivative (340 mg) as a white solid.

The quinoxalinone derivative (101 mg, 0.20 mmol) obtained in the above(1) was suspended in thionyl chloride (1 mL), and N,N-dimethylformamide(15.5 μL, 0.20 mmol) was added thereto. Then, the reaction solution washeated under reflux for 20 minutes. After this reaction solution wascooled to room temperature, the thionyl chloride was removed byevaporation in vacuo. The resulting residue was diluted with ethylacetate, washed successively with water, sodium hydrogencarbonate andsaturated brine. The organic layer was dried over anhydrous magnesiumsulfate, filtered, and concentrated in vacuo to obtain the abovechloroquinoxaline derivative (106 mg) as a pale yellow solid.

The chloroquinoxaline derivative (53 mg, 0.10 mmol) obtained in theabove (2) and chloromethyl methyl ether (23 μL, 0.30 mmol) weredissolved in tetrahydrofuran (2 mL), and then 1.0M tetrahydrofuransolution (0.2 mL, 0.20 mmol) containing tetrabutyl ammonium fluoride wasadded dropwise at room temperature. After the dropwise addition wascompleted, the reaction solution was cooled in an ice-bath, methanol (1mL) was added, and sodium hydride (14 mg, 60% dispersion in oil, 0.35mmol) was gradually added thereto. The resulting reaction solution wasstirred at room temperature for 1 hour, and saturated aqueous ammoniumchloride was added to stop the reaction. The whole reaction solution waspoured into water, and extracted with ethyl acetate. The organic layerwas washed successively with water and saturated brine. Then, theorganic layer was dried over anhydrous magnesium sulfate, filtered, andconcentrated in vacuo to obtain the above methoxyquinoxaline derivative(49 mg) as a white solid.

The methoxyquinoxaline derivative (45 mg, 100 μmol) obtained in theabove (3) was dissolved in toluene (3 mL), and to this solution wereadded tributylvinyltin (36 μL, 120 μmol) andtetrakis(triphenylphosphine)palladium(0) (16 mg, 2.5 μmol). The mixturewas heated at reflux for 4 hours. The resulting reaction solution wascooled down to room temperature, and filtered through a Celite pad. Thefiltrate was concentrated in vacuo, and the resulting residue waspurified by thin layer chromatography to obtain the above vinylderivative (30 mg) as a pale yellow solid.

To acetonitrile solution (3 mL) containing the vinyl derivative (20 mg,50 μmol) obtained in the above (4) were added water (1 mL), 50% aqueoussolution (15 μL, 65 μmol) of N-methylmorpholine N-oxide, and 0.05Maqueous osmium tetraoxide solution (50 μL, 0.25 μmol). After theresulting solution was stirred at room temperature for 16 hours,saturated aqueous sodium thiosulfate solution was added thereto, and themixture was stirred at room temperature for 30 minutes. After thissolution was extracted with ethyl acetate, the organic layer was washedwith saturated brine, dried over anhydrous magnesium sulfate, filtered,and concentrated. The resulting residue was purified by a thin layerchromatography to obtain the above diol derivative (18 mg) as a paleyellow solid.

To tetrahydrofuran solution (2 mL) containing the diol derivative (18mg) obtained in the above (5) were added water (2 mL) and potassiumperiodate (13 mg, 54 μmol). The resulting mixture was stirred at roomtemperature for 2 hours, and water was added thereto. This solution wasextracted with ethyl acetate, and the organic layer was washed withsaturated brine. Then, the organic layer was dried over anhydrousmagnesium sulfate, filtered, and the filtrate was concentrated. Theresulting residue was purified by a thin layer chromatography to obtainthe above aldehyde derivative (12 mg) as a pale yellow solid.

The aldehyde derivative (640 mg, 1.59 mmol) obtained in the above (6)was dissolved in chloroform (15 mL) and methanol (10 mL), and thensodium tetrahydroborate (120 mg, 3.18 mmol) was added thereto underice-cooling. The resulting reaction solution was stirred for 15 minutesunder ice-cooling. After saturated aqueous ammonium chloride was addedto the reaction solution, the mixture was extracted with chloroform. Theorganic layer was washed successively with water and saturated brine,dried over anhydrous magnesium sulfate, filtered, and concentrated. Theresulting residue was purified by a column chromatography on silica gelto obtain the above benzyl alcohol derivative (416 mg) as a pale yellowsolid.

The benzyl alcohol derivative (11.0 g, 27.3 mmol) obtained in the above(7) was dissolved in chloroform (120 mL), and to this solution wereadded 3,4-dihydro-2H-pyran (60 mL) and pyridinium p-toluenesulfonate(1.50 g, 5.97 mmol) at room temperature. The resulting reaction solutionwas stirred at room temperature for 4 hours, and diluted with ethylacetate. The organic layer was washed successively with aqueous sodiumhydrogencarbonate and saturated brine, dried over anhydrous magnesiumsulfate, filtered, and concentrated in vacuo to obtain the abovetetrahydropyranyl ether derivative (11.1 g) as a white solid.

The tetrahydropyranyl ether derivative (3.00 g, 6.17 mmol) obtained inthe above (8) was dissolved in tetrahydrofuran (50 mL) and methanol (50mL), and then 1N aqueous sodium hydroxide (50 mL) was added. The mixturewas stirred for 30 minutes. The resulting reaction solution was dilutedwith ethyl acetate, and washed successively with 1N hydrochloric acid,water, and saturated brine. The resulting organic layer was dried overanhydrous magnesium sulfate, filtered, and concentrated in vacuo toobtain the above carboxylic acid derivative (3.00 g) as a white solid.

To chloroform solution (60 mL) containing the carboxylic acid derivative(1.50 g, 3.17 mmol) obtained in the above (9) was added pyridine (1.54mL, 19.0 mmol), and then chloroform solution (10 mL) containing2-chloro-1,3-dimethylimidazolinium chloride (1.07 g, 6.35 mmol) wasadded dropwise thereto with stirring under ice-cooling. The mixture wasstirred at room temperature for 15 minutes. After that, chloroformsolution(20 mL) containing the hydrazine derivative [A-17] (2.59 g, 9.51mmol) was added to the solution, and the mixture was stirred at roomtemperature for 5 hours. Water was added to the resulting reactionsolution, and the mixture was extracted with ethyl acetate. The organiclayer was washed successively with 1N hydrochloric acid, water, andsaturated brine, and purified by a silica gel chromatography to obtainthe above hydrazide derivative (1.59 g) as a pale yellow oil.

To tetrahydrofuran solution (20 mL) containing the hydrazide derivative(1.59 g, 2.18 mmol) obtained in the above (10) were added diethylamine(1.13 mL, 10.9 mmol) and formic acid (0.411 mL), and thentetrakis(triphenylphosphine)palladium(0) (252 mg, 0.218 mmol) was addedthereto. After stirring the solution at room temperature for 2 hours,water was added to the reaction solution, and the mixture was extractedwith ethyl acetate. The organic layer was washed successively withaqueous sodium hydrogencarbonate, water, and saturated brine, andpurified by a silica gel chromatography to obtain the above de-Allocderivative (1.10 g) as a pale yellow oil.

N,N-diisopropylethylamine (509 μL, 2.92 mmol) was added toN,N-dimethylformamide solution (50 mL) containing the de-Allocderivative (628 mg, 974 μmol) obtained in the above (11), and themixture was stirred at 120° C. for 3 hours. After that, the resultingreaction solution was cooled down to room temperature, and concentratedin vacuo. Chloroform (10 mL) was added to the resulting residue, and theresulting solid was filtered off. This solid was dried in vacuo toobtain the above 3-indazolinone derivative (251 mg) as a yellow solid.

To chloroform solution (10 mL) containing the 3-indazolinone derivative(250 mg, 489 μmol) obtained in the above (12) was addedN,N-diisopropylethylamine (426 μL, 2.45 mmol), and then methanesulfonylchloride (113 μL, 1.47 mmol) was added thereto, followed by stirring for30 minutes under ice-cooling. After addition of water to the resultingreaction solution, the organic layer was separated, and washedsuccessively with 0.5N hydrochloric acid, water, and saturated brine.Then, the organic layer was dried over anhydrous magnesium sulfate,filtered, and concentrated. The resulting residue was dissolved inN-methylpyrrolidone (2.5 mL), and then(R)-3-hydroxypyrrolidine (250 mg,2.87 mmol) was added. The mixture was stirred at 70° C. for 1 hour, andcooled down to room temperature. After that, aqueous sodiumhydrogencarbonate was added to the solution, and the solution wasextracted with ethyl acetate, and washed successively with water andsaturated brine. The organic layer was dried over anhydrous magnesiumsulfate, filtered, and concentrated. The resulting residue was purifiedby a silica gel chromatography to obtain the above amine (176 mg) as ayellow solid.

N,N-diisopropylethylamine (264 μL, 1.52 mmol) was added totetrahydrofuran solution (3.5 mL) of the amine derivative (176 mg, 303μmol) obtained in the above (13), and then methanesulfonyl chloride(70.5 μL, 910 μmol) was added thereto under ice-cooling. The solutionwas stirred for 30 minutes under ice-cooling, and 1N aqueous sodiumhydroxide (3.5 mL) was added dropwise to the solution, followed byaddition of methanol (3.5 mL). The solution was stirred for 15 minutesunder ice-cooling, and then water was added. The solution was extractedwith chloroform, and washed with saturated brine. The organic layer wasdried over anhydrous magnesium sulfate, filtered, and concentrated toobtain the above mesylated derivative (170 mg) as a yellow solid.

The mesylated derivative (170 mg, 258 μmol) obtained in the above (14)was dissolved in trifluoroacetic acid (15 mL) and water (1.5 mL), andthe solution was stirred at room temperature for 1 hour. The resultingreaction solution was concentrated in vacuo, followed by azeotropicevaporation with ethanol and toluene to obtain the above phenolderivative (170 mg) as a yellow solid.

The phenol (170 mg) obtained in the above (15) was dissolved inN,N-dimethylformamide (35 mL), and then potassium carbonate (400 mg,2.89 mmol) was added thereto. The mixture was stirred at 70° C. for 1.5hours. The resulting reaction solution was cooled down to roomtemperature, filtered, and the mother liquor was concentrated in vacuo.The resulting residue was dissolved in a mixed solution of chloroformand methanol, and washed with saturated brine. The organic layer wasdried over anhydrous magnesium sulfate, filtered, and concentrated. Theresulting residue obtained again was purified by a silica gelchromatography to obtain the above cyclic derivative (92 mg) as a yellowsolid.

The cyclic compound (30 mg, 69 μmol) prepared in the above (16) wasdissolved in chloroform (1 mL), and to this solution were addedN,N-diisopropylethylamine (48 μL, 276 μmol) and methanesulfonyl chloride(13 μL, 173 μmol), then the mixture was stirred for 30 minutes. Anaqueous solution (1 mL) in which sodium hydrogencarbonate (60 mg) wasdissolved was added to the reaction solution. In addition, after theamine [A-23] (30 mg) was added to the solution, the mixture was stirredat 60° C. for 1 hour. The reaction solution was cooled down to roomtemperature, and the organic layer was separated, concentrated, andpurified by a thin layer chromatography to obtain the above benzylaminederivative (30 mg) as a yellow solid.

The benzylamine derivative obtained in the above (17) was dissolved intrifluoroacetic acid (5 mL) and water (500 μL), and the solution washeated at reflux for 3 days. The reaction solution was cooled down toroom temperature, and concentrated in vacuo. After the resulting residuewas dissolved in a mixed solution of chloroform and methanol, thesolution was washed successively with water and saturated brine. Theorganic layer was dried over anhydrous magnesium sulfate, filtered, andconcentrated. The resulting residue was purified by thin layerchromatography to give a yellow solid. To a stirred solution of thesolid in chloroform (5 mL) was added dropwise 4N hydrogenchloride/1,4-dioxan solution (500 μL), and the resulting precipitateswere collected by filtration, washed with diethyl ether, and dried invacuo to obtain the hydrochloride (26 mg) of the objective compound [11]as a yellow solid.

Spectral data of the compound of the above formula [11] are shown below.

¹H-NMR(DMSO-d₆)δ:1.50-4.50(24H,m),5.15-5.35(1H,m),7.00-7.50(3H,m),7.86(1H,d,J=7.8Hz),9.25(1H,bs),9.51-9.68(1H,brs),11.8(1H,brs),12.9(1H,brs).

mass:517(M+1)⁺.

Working Example 12

Synthesis of the Compound of the Following Formula [12]:

According to a method similar to the procedures described in WorkingExamples 11-(17) to 11-(18), the hydrochloride (26 mg) of the objectivecompound [12] was obtained as an orange solid from the cyclic derivative(30 mg, 69 μmol) obtained in Working Example 11-(16) and the aminederivative [A-24].

Spectral data of the compound of the above formula [12] are shown below.

¹H-NMR(DMSO-d₆)δ:1.50-4.50(24H,m),5.15-5.35(1H,m),7.00-7.50(3H,m),7.86(1H,d,J=7.8Hz),9.25(1H,bs),9.51-9.68(1H,brs),11.8(1H,brs),12.9(1H,brs).

mass:517(M+1)⁺.

Working Example 13

Synthesis of the Compound of the Following Formula [13]:

According to a method similar to the procedures described in WorkingExamples 11-(17) to 11-(18), the hydrochloride (25 mg) of the objectivecompound [13] was obtained as an orange solid from the cyclic compoundderivative (30 mg, 69 μmol) obtained in Working Example 11-(16) andmorpholine.

Spectral data of the compound of the above formula [13] are shown below.

¹H-NMR(DMSO-d₆)δ:1.60-4.20(18H,m),4.41(2H,s),5.15-5.40(1H,m),7.00-7.96(4H,m),9.10-9.40(1H,m),10.8-12.0(2H,m),12.8-13.0(1H,m).

mass:489(M+1)⁺.

Working Example 14

Synthesis of the Compound of the Following Formula [14]:

The quinoxalinone derivative (100 mg, 0.20 mmol) obtained in WorkingExample 11-(1) was dissolved in tetrahydrofuran (5 mL), and thenchloromethyl 2-(trimethylsilyl)ethyl ether (37 pL, 0.30 mmol) was addedto the solution. Then, the solution was stirred at room temperature, andto this solution was added potassium t-butoxide (29 mg, 0.26 mmol) at 0°C. The resulting reaction solution was warmed up to room temperature,and stirred for 30 minutes. After chloromethyl 2-(trimethylsilyl)ethylether (37 μL, 0.30 mmol) was added thereto, and then 1Mtetrabutylammonium fluoride/tetrahydrofuran (260 μL, 0.26 mmol) wasadded thereto. The resulting reaction solution was stirred at roomtemperature for 40 minutes. Then chloromethyl 2-(trimethylsilyl)ethylether (37 μL, 0.30 mmol) was added thereto, and the mixture was stirredat room temperature for 2 hours. Water was added to the resultingreaction solution, and the solution was extracted with chloroform, andthe extract was washed with saturated brine. The organic layer was driedover anhydrous magnesium sulfate, filtered in vacuo, and concentrated.The resulting residue was purified by a thin layer chromatography onsilica gel to obtain the above protected derivative with SEM (83 mg) asa white solid.

According to a method similar to the procedures described in WorkingExample 1-(1), the above carboxylic acid derivative (121 mg) wasobtained as a pale yellow solid from the protected derivative with SEM(100 mg, 0.15 mmol) obtained in the above (1).

The carboxylic acid derivative (3.78 g, 5.08 mmol) obtained in the above(2) was dissolved in chloroform (30 mL), and to this solution were added1-hydroxybenzotriazole (1.01-g, 6.60 mmol) and1-{(3-dimethylamino)propyl}-3-ethylcarbodiimide hydrochloride (1.36 g,6.60 mmol). After this solution was stirred at room temperature for 5minutes, 3-aminopropionitrile (0.49 mL, 6.60 mmol) was added thereto.The resulting solution was stirred at the same temperature for 4 hours,diluted with chloroform, and washed successively with aqueous sodiumhydrogencarbonate and saturated aqueous ammonium chloride. The resultingorganic layer was dried over anhydrous magnesium sulfate, filtered, andconcentrated. The resulting residue was purified by a columnchromatography on silica gel to obtain the above amide derivative (3.28g) as a pale yellow solid.

According to a method similar to the procedure described in WorkingExample 1-(3), the above benzisothiazolone derivative (2.93 g) wasobtained as a yellow solid from the amide derivative (3.28 g, 4.12 mmol)obtained in the above (3).

The benzoisothiazolone derivative (2.33 g, 3.31 mmol) obtained in theabove (4) was dissolved in a mixed solution of N,N-dimethylformamide (25mL) and methanol (25 mL), and then sodium hydrogencarbonate (800 mg,9.93 mmol) was added. After substituting the reaction system withnitrogen gas, palladium(II) acetate (75 mg, 0.33 mmol) and1,1′-bis(diphenylphosphino)ferrocene (185 mg, 0.33 mmol) were added tothe reaction solution at room temperature under a nitrogen atmosphere.Then, the atmosphere in the reaction system was substituted with carbonmonooxide. This reaction solution was stirred at 70° C. for 2 hours,cooled down to room temperature, diluted with chloroform, and washedsuccessively with water and saturated aqueous ammonium chloride. Theresulting organic layer was dried over anhydrous magnesium sulfate,filtered, and concentrated. The resulting residue was purified by acolumn chromatography on silica gel to obtain the above ester derivative(2.03 g) as a yellow solid.

The ester derivative (2.03 g, 2.97 mmol) obtained in the above (5) wasdissolved in a mixed solution of tetrahydrofuran (150 mL) and methanol(50 mL), and then 1N sodium hydroxide (50 mL) was added thereto at roomtemperature. After the resulting reaction solution was stirred at roomtemperature for 1 hour, the pH of the solution was adjusted to 2 using1N hydrochloric acid. After removal of the tetrahydrofuran and methanolfrom the solution by evaporation in vacuo, the resulting precipitateswere filtered off. The precipitates were washed with water, and dried invacuo to obtain the above carboxylic acid derivative (1.78 g) as ayellow solid.

The carboxylic acid derivative (50 mg, 75 μmol) obtained in the above(6) was dissolved in tetrahydrofuran (5 mL), and to this solution wereadded benzotriazo-1-yloxytripyrrolidinophosphonium hexafluorophosphate(47 mg, 90 pmol) and N,N-diisopropylethylamine (17 μL, 97 μmol) at roomtemperature. After the resulting reaction solution was stirred at thesame temperature for 5 minutes, 2M tetrahydrofuran solution (80 μL)containing lithium tetrahydroborate was added, and the solution wasstirred for 20 minutes. This reaction solution was poured into aqueousammonium chloride solution, and extracted with chloroform. The organiclayer was dried over anhydrous magnesium sulfate, filtered, andconcentrated. The resulting residue was purified by a thin layerchromatography to obtain the above benzyl alcohol derivative (33.5 mg)as a pale yellow oil.

The benzyl alcohol derivative (675 mg, 1.03 mmol) obtained in the above(7) was dissolved in N,N-dimethylformamide (8 mL), and to the solutionwere added successively imidazole (106 mg, 1.55 mmol) andt-butyldimethylsilyl chloride (202 mg, 1.34 mmol) in an ice-bath, andthen the reaction solution was stirred at room temperature overnight.The resulting reaction solution was diluted with ethyl acetate, andwashed successively with water and saturated brine. The organic layerwas dried over anhydrous magnesium sulfate, filtered, and concentratedin vacuo to obtain the above protected derivative with TBS (812 mg) as ayellow oil.

The protected derivative (78 mg) with TBS obtained in the above (8) wasdissolved in tetrahydrofuran (2 mL), and to this solution was dropwiseadded 1M tetrahydrofuran solution (0.30 mL, 0.30 mmol) containinglithium hexamethyldisilazide in an ice-bath. After the resultingsolution was stirred for 20 minutes in an ice-bath, saturated aqueousammonium chloride was added thereto to stop the reaction. The wholesolution was poured into water, extracted with ethyl acetate, and theorganic layer was washed successively with water and saturated brine.The organic layer was dried over anhydrous magnesium sulfate, filtered,and concentrated in vacuo to obtain the above de-propionitrilederivative (73 mg) as an orange solid.

The de-propionitrile derivative (296 mg) obtained in the above (9) andthe mesylated derivative [A-5] (258 mg) were dissolved in 1,4-dioxane(15 mL), and then 4N aqueous lithium hydroxide (103 μL, 413 μmol) wasadded to the solution. After the solution was heated at reflux for 5hours, it was cooled down to room temperature, and 4N aqueous lithiumhydroxide (824 μL, 3.30 mmol) was added thereto, whereby the reactionsolution was suspended. After 1,4-dioxan and water were added to thereaction solution to dissolve the suspension, the solution was heated atreflux for 1 hour. Then, the reaction solution was cooled down to roomtemperature, and saturated aqueous ammonium chloride was added thereto.The solution was extracted with chloroform. The resulting organic layerwas washed with saturated brine, dried over anhydrous magnesium sulfate,and filtered. The filtrate was concentrated, and the resulting residuewas purified by a column chromatography on silica gel to obtain theabove N-alkylbenzoisothiazolone derivative (247 mg) as a yellow solid.

The N-alkylbenzoisothiazolone derivative (247 mg, 346 pmol) obtained inthe above (10) was dissolved in chloroform (25 mL), and to the solutionwere added successively imidazole (28 mg, 415 μmol) andt-butyldimethylsilyl chloride (52 mg, 346 μmol) in an ice-bath. Thereaction solution was stirred overnight at room temperature. Theresulting reaction solution was diluted with ethyl acetate, and washedsuccessively with water and saturated brine. The organic layer was driedover anhydrous magnesium sulfate, filtered, and concentrated in vacuo.The resulting residue was purified by a chromatography on silica gel toobtain the above protected derivative (170 mg) with TBS as a yellowsolid.

The protected derivative (170 mg, 205 μmol) with TBS obtained in theabove (11) was dissolved in chloroform (5 mL), and to the solution wereadded triethylamine (57 μL, 410 μmol) and methanesulfonyl chloride(24μL, 308 μmol) under ice-cooling, and the mixture was stirred for 1 hour.After aqueous sodium hydrogencarbonate was added the resulting reactionsolution, the mixture was extracted with chloroform. This organic layerwas washed with saturated brine, dried over anhydrous magnesium sulfate,and filtered. The filtrate was concentrated to obtain a yellow oil. Theresulting yellow oil was dissolved in chloroform (4 mL) and methanol (2mL), and then 4N hydrogen chloride in 1,4-dioxane (4 mL) was addedthereto. The solution was stirred for 3 hours at room temperature. Thissolution was neutralized with aqueous sodium hydrogencarbonate underice-cooling, extracted with chloroform, and the organic layer was washedwith saturated brine. After the organic layer was filtered, it wasconcentrated. The resulting residue was purified by a columnchromatography on silica gel to obtain the above mesylated derivative(82mg) as a yellow solid.

The mesylated derivative (82 mg, 154 μmol) obtained in the above (12)was dissolved in N-methylpyrrolidone (4 mL), and to the solution wasadded potassium carbonate (64 mg, 462 μmol). The solution was stirred at90° C. for 5 hours. The resulting reaction was cooled down to roomtemperature, and ethyl acetate was added thereto. The organic layer waswashed successively with water and saturated brine. After the solutionwas filtered and the filtrate was concentrated, and the resultingresidue was purified by a thin layer chromatography to obtain the abovecyclic derivative (23 mg) as a yellow solid.

The cyclic derivative (23 mg, 40.6 μmol) obtained in the above (13) wasdissolved in chloroform (1 mL), and to the solution were addedtriethylamine (11 μL, 81.3 μmol) and methanesulfonyl chloride (6.3 μL,81.3 μmol) under ice-cooling. After stirring the solution for 30minutes, piperidine (40 μL, 406 μmol) was added to the resultingreaction solution. The mixture was heated at reflux for 30 minutes. Thereaction solution was cooled down to room temperature, and purified by athin layer chromatography to obtain the above benzylamine derivative (24mg) as a yellow solid.

According to a method similar to the procedure described in WorkingExample 1-(6), the hydrochloride (21 mg) of the objective compound [14]was obtained from the benzylamine derivative (21 mg) obtained in theabove (14).

Spectral data of the compound of the above formula [14] are shown below.

¹H-NMR(DMSO-d₆)δ:1.30-1.47(1H,m),1.60-2.39(14H,m),2.80-3.00(2H,m),3.25-3.40(2H,m),3.70-4.22(2H,m),4.30-4.45(2H,m),5.39(1H,m),7.02(1H,s),7.43(1H,s),7.65(1H,t,J=7.7 Hz),8.06(1H,d,J=7.7Hz),9.30(1H,d,J=7.7 Hz),10.2(1H,brs),13.0(1H,s).

mass:503(M+1)⁺.

Working Example 15

Synthesis of the Compound of the Following Formula [15]:

In the above formula, the stereo chemistry of the position with thesymbol * is of cis-configuration(hereinafter, the same until WorkingExample 19).

According to a method similar to the procedure described in WorkingExample 11-(8), the above tetrahydropyranyl ether derivative (78 mg) wasobtained as a yellow solid from the benzyl alcohol derivative (65 mg,0.10 mmol) obtained in Working Example

According to a method similar to the procedure described in WorkingExample 14-(9), the above de-propionitrile derivative (73 mg) wasobtained as an orange solid from the tetrahydropyranyl ether derivative(78 mg, 0.10 mmol) obtained in the above (1).

According to a method similar to the procedure described in WorkingExample 14-(10), the above racemic N-alkylbenzoisothiazolone derivative(1.4 g) was obtained as a yellow solid from the de-propionitrilederivative (3.1 g, 4.6 mmol) and the racemic mesylated derivative [A-12](3.7 g, 9.2 mmol) obtained in the above (2).

The racemic N-alkylbenzoisothiazolone derivative (2.2 g, 2.2 mmol)obtained in the above (3) was dissolved in tetrahydrofuran (30 mL), andto the solution was added 1M tetrahydrofuran solution (16 mL) containingtetrabutylammonium fluoride. The solution was stirred at roomtemperature for 2 hours. The resulting reaction solution was dilutedwith chloroform (150 mL), and washed with 0.1M phosphate buffer (pH 6.8)and saturated brine. The organic layer was dried over anhydrousmagnesium sulfate, filtered, and the filtrate was concentrated. Theresulting residue was purified by a column chromatography on silica gelto obtain the above racemic alcohol derivative(1.53 g) as a yellowsolid.

According to a method similar to the procedures described in WorkingExamples 14-(12) to 14-(13), the above racemic cyclic derivative (124mg) was obtained as a yellow solid from the racemic alcohol derivative(1.53 g, 1.7 mmol) obtained in the above (4).

According to a method similar to the procedure described in WorkingExample 14-(14), the above benzylamine derivative as a diastereomermixture (64 mg) was obtained as a yellow oil from the racemic cyclicderivative (100 mg, 150 μmol) and the racemic amine derivative [A-25]obtained in the above (5).

The above benzylamine derivative as a diastereomer mixture (64 mg, 80mmol) obtained in the above (6) was dissolved in chloroform (1 mL), andto the solution were added dichlorobis(triphenylphosphine)palladium(II)(23 mg, 30 μmol), acetic acid (20 mg, 340 μmol), tributyltin hydride (73mg, 250 μmol). The mixture was stirred at room temperature for 30minutes. The resulting reaction solution was purified by a thin layerchromatography to obtain the above de-Alloc derivative as a diastereomermixture (50 mg) as a yellow oil.

According to a method similar to the procedure described in WorkingExample 1-(6), the above hydrochloride (27 mg) of the objective compound[15] as a diastereomer mixture was obtained as a yellow solid from thede-Alloc derivative (50 mg, 70 μmol) as a diastereomer mixture obtainedin the above (7).

Spectral data of the compound of the above formula [15] are shown below.

¹H-NMR(DMSO-d₆)δ:1.60-2.40(9H,m),2.60-3.80(11H,m),4.20-4.80<(6H,m),7.15(1H,J=4.8Hz),7.75(2H,m),8.18(1H,d,J=7.7 Hz),9.43(1H,d,J=7.7Hz).11.2(1H,brs),13.2(1H,brs).

mass:548(M+1)⁺.

Working Example 16

Synthesis of the Compound of the Following Formula [16]:

According to a method similar to the procedure described in WorkingExample 6-(1), the hydrochloride (6.4 mg) of the objective compound [16]as a diastereomer mixture was obtained as a yellow solid from thecompound (10 mg, 20 mmol) obtained as a diastereomer mixture in WorkingExample 15.

Spectral data of the compound of the above formula [16] are shown below.

¹H-NMR(DMSO-d₆)δ:1.60-2.20(9H,m),2.20-3.00(4H,m),3.00-3.80(10H,m),4.00-4.60(6H,m),7.06(1H,s),7.60(2H,m),8.07(1H,d,J=7.6Hz),9.37(1H,d,J=7.6 Hz), 10.0(H,brs),13.0(1H,brs) mass:562(M+1)⁺.

Working Example 17

Synthesis of the Compound of the Following Formula [17]:

According to a method similar to the procedure described in WorkingExample 14-(14), the above benzylamine derivative (183 mg) as adiastereomer mixture was obtained as a yellow oil from the racemiccyclic derivative (210 mg, 320 μmol) obtained in Working Example 15-(5)and the racemic amine derivative [A-22] (147 mg, 970 μmol).

According to a method similar to the procedure described in WorkingExample 15-(7), the above de-Alloc derivative (131 mg) as a diastereomermixture was obtained as a yellow oil from the benzylamine derivative asa diastereomer mixture (183 mg, 240 μmol) obtained in the above (1).

According to a method similar to the procedure described in WorkingExample 11-(18), the hydrochloride (51.4 mg) of the objective compound[17] was obtained as a yellow solid from the de-Alloc derivative (131mg, 240 μmol) as a diastereomer mixture obtained in the above (2).

Spectral data of the compound of the above formula [17] are shown below.

¹H-NMR(DMSO-d₆)δ:1.60-2.40(12H,m),3.20-3.80(7H,m),4.20-4.80(5H,m),7.20(1H,m),7.75(2H,m),8.18(1H,d,J=8.0 Hz),9.42(1H,d,J=8.0Hz),9.80(1H,brs),11.7(1H,brs).

mass:534(M+1)⁺.

Working Example 18

Synthesis of the Compound of the Following Formula [18]:

According to a method similar to the procedure described in WorkingExample 14-(14), the above racemic benzylamine derivative (22 mg) wasobtained as a yellow solid from the racemic cyclic derivative (65 mg,100 μmol) obtained in the Working Example 15-(5) and piperidine.

The racemic benzylamine derivative (22 mg, 30 μmol) obtained in theabove (1) was dissolved in tetrahydrofuran (1 mL), and to the solutionwere added formic acid (7 mg, 150 μmol), diethylamine (16 μL, 830 μmol)and tetrakis(triphenylphosphine)palladium(0) (1.73 mg, 1.5 μmol) underice-cooling. The mixture was stirred at room temperature for 3 hours.Aqueous sodium hydrogencarbonate was added to the resulting reactionsolution, followed by extraction with chloroform. The organic layer waswashed with saturated brine, dried over anhydrous magnesium sulfate, andfiltered. The filtrate was concentrated, and purified by a thin layerchromatography to obtain the above racemic N-allyl derivative (7.1 mg,11 μmol) as a yellow solid and the above racemic N—H derivative (6.9 mg)as a yellow solid, respectively.

According to a method similar to the procedure described in WorkingExample 1-(6), the hydrochloride (5.6 mg) of the racemic objectivederivative [18] was obtained as a yellow solid from the racemic N—Hderivative (6.9 mg, 11 μmol) obtained in the above (2).

Spectral data of the compound of the above formula [18] are shown below.

¹H-NMR(DMSO-d₆)δ:1.20-2.50(10H,m),2.60-3.80(4H,m),4.20-4.80(8H,m),7.17(1H,s),7.75(1H,t,J=7.7 Hz),7.75(1H,s),8.18(1H,d,J=7.7Hz),9.42(1H,d,J=7.7 Hz),11.2(1H,brs),13.2(1H,brs).

mass:506(M+1)⁺.

Working Example 19

Synthesis of the Compound of the Following Formula:

According to a method similar to the procedure described in WorkingExample 1-(6), the hydrochloride (4.5 mg, 11 μmol) of the racemicobjective derivative [19] was obtained as a yellow solid from theracemic N-allyl derivative (7.1 mg, 11 μmol) obtained in Working Example18-(2).

Spectral data of the compound of the above formula [19] are shown below.

¹H-NMR(DMSO-d₆)δ:1.20-2.20(10H,m),2.20-3.10(4H,m),3.10-4.60(10H,m),5.10-5.40(2H,m),6.05(1H,m),7.06(1H,s),7.51(1H,s),7.63(1H,t,J=7.5Hz),8.06(1H,d,J=7.7 Hz),9.37(1H,d,J=7.7 Hz),10.8 (1H,brs),13.0(1H,brs).

mass:544(M+1)⁺.

Working Example 20

Synthesis of the Compound of the Following Formula [20]:

According to a method similar to the procedures described in WorkingExample 15-(3) to 15-(5), the above cyclic derivative (82 mg) wasobtained as an orange solid from the de-propionitrile derivative (617mg, 0.900 mmol) obtained in the Working Example 15-(2) and the mesylatedderivative [A-13].

According to a method similar to the procedures described in WorkingExamples 14-(14) and 1-(6), the hydrochloride (36 mg) of the objectivecompound [20] was obtained as a yellow solid from the cyclic derivative(82 mg, 0.145 mmol) obtained in the above (1).

Spectral data of the compound of the above formula [20] are shown below.¹H-NMR(DMSO-d₆)δ:1.30-2.10(13H,m),2.90-3.10(4H,m),3.30-3.40(2H,m),4.20-4.40(4H,m),4.83(1H,s),7.05(1H,s),7.39(1H,s),7.63(1H,t,J=8.0Hz),8.09(1H,d,J=8.0 Hz),9.18(1H,d,J=8.0 Hz),10.6(1H,brs),13.0(1H,s).

mass:503(M+1)⁺.

Working Example 21

Synthesis of the Compound of the Following Formula [21]:

According to a method similar to the procedures described in WorkingExample 20, the hydrochloride (90 mg) of the objective compound [21] wasobtained as a yellow solid from the de-propionitrile derivative (547 mg,0.797 mmol) obtained in the Example 15-(2) and the mesylated derivative[A-8].

Spectral data of the compound of the above formula [21] are shown below.

¹H-NMR(DMSO-d₆)δ:1.23(3H,d,J=8.0 Hz),1.30-2.00(9H,m),2.30-2.60(3H,m),2.80-3.00(2H,m),3.20-3.40(2H,m),4.15(1H,t,J=10.0Hz),4.30-4.60(4H,m),7.03(1H,s),7.51(1H,s),7.62(1H,t,J=8.0 Hz),8.03(1H,d,J=8.0 Hz),9.41(1H,d,J=8.0 Hz),10.8(1H,brs),13.1(1H, s).

mass:491(M+1)⁺.

Working Example 22

Synthesis of the Compound of the Following Formula [22]:

According to a method similar to the procedure described in WorkingExample 20, the hydrochloride (130 mg) of the objective compound [22]was obtained as a yellow solid from the de-propionitrile derivative (755mg, 1.10 mol) obtained in the Working Example 15-(2) and the mesylatedderivative [A-9].

Spectral data of the compound of the above formula [22] are shown below.

¹H-NMR(DMSO-d₆)δ:1.22(3H,d,J=8.0Hz),1.30-2.00(9H,m),2.30-2.60(3H,m),2.80-3.00(2H,m),3.20-3.40(2H,m),4.14(1H,t,J=10.0Hz),4.32-4.34(2H,m),4.43-4.48(1H,m),4.55-4.60(1H,m),7.02(1H,s),7.50(1H,s),7.61(1H,t,J=8.0Hz),8.02(1H,d,J=8.0 Hz),9.40(1H, d,J=8.0 Hz),10.8(1H,brs),13.0(1H,s).

mass:491(M+1)⁺.

Working Example 23

Synthesis of the Compound of the Following Formula [23]:

According to a method similar to the procedure described in WorkingExample 20, the hydrochloride (59 mg) of the objective compound [23] wasobtained as a yellow solid from the de-propionitrile derivative (523 mg,762 μmol) obtained in Working Example 15-(2) and the mesylatedderivative [A-4].

Spectral data of the compound of the above formula [23] are shown below.

¹H-NMR(DMSO-d₆)δ:1.50-1.70(1H,m),1.90-2.30(8H,m),2.40-2.58(2H,m),2.60-3.00(4H,m),3.10-3.30(2H,m),3.50-3.80(2H,m),4.58-4.64(3H,m),4.82-5.00(1H,m),5.18-5.22(1H,m),7.36(1H,s),7.80(1H,s),7.90(1H,t,J=7.7Hz),8.30(1H,d,J=7.7 Hz)9.54(1H,d,J=7.7H z),13.2(1H,s).

mass:503(M+1)⁺.

Working Example 24

Synthesis of the Compound of the Following Formula [24]:

According to a method similar to the same procedure as Working Example23, the hydrochloride (59 mg) of the objective compound [24] wasobtained from the de-propionitrile derivative obtained in WorkingExample 15-(2) and the mesylated derivative [A-6].

Spectral data of the compound of the above formula [24] are shown below.

¹H-NMR(DMSO-d₆)δ:1.50-1.70(1H,m),1.90-2.30(8H,m),2.40-2.58(2H,m),2.60-3.00(4H,m),3.10-3.30(2H,m),3.50-3.80(2H,m),4.58-4.64(3H,m),4.82-5.00(1H,m),5.18-5.22(1H,m),7.36(1H,s),7.80(1H,s),7.90(1H,t,J=7.7Hz),8.30(1H,d,J=7.7 Hz)9.54(1H,d,J=7.7H z),10.8(1H,brs),13.2(1H,s).

mass:503(M+1)⁺.

Working Example 25

Synthesis of the Compound of the Following Formula [25]:

According to a method similar to the procedures described in WorkingExamples 14-(10) to 14-(14) and 1-(6), the hydrochloride (14 mg) of theobjective compound [25] was obtained as a yellow solid from thede-propionitrile derivative (145 mg) obtained in Working Example 14-(9)and the mesylated derivative [A-7] (193 mg).

Spectral data of the compound of the above formula [25] are shown below.

¹HNMR(DMSO-d₆)δ:1.30-1.55(2H,m),1.60-1.75(4H,m),1.75-2.05(5H,m),2.32(2H,m),2.65(4H,m),2.85-2.95(2H,m),4.00-4.15(1H,m),4.30-4.40(2H,m),4.50-4.60(1H,m),5.27(1H,m),7.00(1H,s),7.16(1H,s),7.63(1H,m),8.08(1H,d,J=7.6Hz),9.31(1H,d,J=7.2 Hz),9.88 (1H,brs).

mass:503(M+1)⁺.

Working Example 26

Synthesis of the Compound of the Following Formula [26]:

According to a method similar to the procedures described in WorkingExamples 14-(10) to 4-(14), and 1-(6), the hydrochloride (63.9 mg) ofthe objective compound [26] was obtained as a yellow solid from thede-propionitrile derivative (456 mg, 637 μmol) obtained in WorkingExample 14-(9) and the mesylated derivative [A-10].

Spectral data of the compound of the above formula [26] are shown below.

¹H-NMR(DMSO-d₆)δ:1.39-1.50(4H,m),1.69-1.86(7H,m),2.08-2.11(4H,m),2.88-2.93(2H,m),3.25-3.37(2H,m),3.55-3.70(1H,m),4.01-4.41(3H,m),4.91-4.92(1H,m),6.96(1H,s),7.44(1H,s),7.50-7.62(1H,m),7.95(1H,d,J=7.3Hz),9.27(1H,d,J=8.1 Hz),13.0(1H,brs).

mass:491(M+1)⁺.

Working Example 27

Synthesis of the Compound of the Following Formula [27]:

According to a method similar to the procedure as Working Example 26,the hydrochloride (63 mg) of the objective compound [27] was obtainedfrom the mesylated derivative [A-11] and the de-propionitile derivativeobtained in Working Example 14-(9).

Spectral data of the compound of the above formula [27] are shown below.

¹H-NMR(DMSO-d₆)δ:1.39-1.50(4H,m),1.69-1.86(7H,m),2.08-2.11(4H,m),2.88-2.93(2H,m),3.25-3.37(2H,m),3.55-3.70(1H,m),4.01-4.41(3H,m),4.91-4.92(1H,m),6.96(1H,s),7.44(1H,s),7.50-7.62(1H,m),7.95(1H,d,J=7.3Hz),9.27(1H,d,J=8.1 Hz),13.0(1H,brs).

mass:491(M+1)⁺.

Working Example 28

Synthesis of the Compound of the Following Formula [28]:

According to a method similar to the procedure described in WorkingExample 1-(1), the above carboxylic acid derivative (2.98 g) wasobtained as a white solid from the tetrahydropyranyl ether derivative(3.00 g, 6.17 mmol) obtained in Working Example 11-(8).

According to a method similar to the procedures described in WorkingExamples 1-(2) to 1-(4), the above benzoisothiazolone derivative (120mg) was obtained as a yellow solid from the carboxylic acid derivative(426 mg, 740 μmol) obtained in the above (1) and the amine derivative[A-14].

According to a method similar to the procedure described in WorkingExample 11-(9), the above alcohol derivative (120 mg) was obtained as apale yellow solid from the benzoisothiazolone derivative (120 mg, 171μmol) obtained in the above (2).

According to a method similar to the procedures described in WorkingExamples 14-(12) to 14-(13), the above cyclic derivative (32 mg) wasobtained as a yellow solid from the alcohol derivative (120 mg) obtainedin the above (3).

According to a method similar to the procedures described in WorkingExamples 14-(14) and 11-(18), the above hydrochloride (34 mg) of theobjective compound [28] was obtained as a yellow solid from the cyclicderivative (32 mg, 70.9 μmol) obtained in the above (4) and the aminederivative [A-27].

Spectral data of the compound of the above formula [28] are shown below.

¹H-NMR(DMSO-d₆)δ:1.35-2.10(10H,m),2.20-4.80(16H,m), 7.07(1H,s),7.37(1H,s),7.64(1H,t,J=7.7 Hz),8.07(1H,d,J=7.7 Hz),9.33(1H 10,d,J=7.7Hz),10.3(1H,brs),13.0(1H,brs).

mass:549(M+1)⁺.

Working Example 29

Synthesis of the Compound of the Following Formula [29]:

According to a method similar to the procedures described in WorkingExamples 1-(2) to 1-(3), the above benzoisothiazolone derivative (1.81g) was obtained as a pale yellow solid from the carboxylic acidderivative (1.31 g, 2.26 mmol) obtained in Working Example 28-(1) andthe amine derivative [A-15].

According to a method similar to the procedure described in WorkingExample 15-(4), the above alcohol derivative (1.08 g) was obtained as ayellow solid from the benzoisothiazolone derivative (1.81 g, 1.89 mmol)obtained in the above (1).

According to a method similar to the procedures described in WorkingExamples 14-(12) to 14-(13), the above cyclic derivative (740 mg) wasobtained as a yellow solid from the alcohol derivative (1.08 g, 1.81mmol) obtained in the above (2).

According to a method similar to the procedures described in WorkingExamples 14-(14) and 11-(18), the trifluoroacetate (20 mg) of theobjective compound [29] as a diastereomer mixture was obtained as ayellow solid from the cyclic derivative (42 mg, 93 μmol) obtained in theabove (3) and the racemic amine derivative [A-22].

Spectral data of the compound of the above formula [29] are shown below.

¹H-NMR(DMSO-d₆)δ:1.45-1.95(5H,m),2.25-2.31(2H,m),2.80-3.15(4H,m),3.20-3.29(3H,m),3.57-3.69(2H,m),3.82-3.95(2H,m),4.02-4.43(5H,m),5.60(1H,m),7.11(1H,s),7.43(1H,s),7.61(1H,t,J=7.6Hz),8.05(1H,d,J=7.6 Hz),9.31(1H,d,J=7.6 Hz),9.49(1H,brs),13.0 (1H,brs).

mass:535(M+1)⁺.

Working Example 30

Synthesis of the Compound of the Following Formula [30]:

According to a method similar to the procedures described in WorkingExamples 14-(14) and 11-(18), the trifluoroacetate (17 mg) of theobjective compound [30] as a diastereomer mixture was obtained as ayellow solid from the alcohol derivative (49 mg, 109 μmol) obtained inWorking Example 29-(3) and the racemic amine derivative [A-26].

Spectral data of the compound of the above formula [30] are shown below.

¹H-NMR(DMSO-d₆)δ:1.42-1.65(2H,m),1.64-1.80(3H,m),1.94(1H,m),2.80-3.15(3H,m),3.40(3H,m),3.55-3.65(4H,m),3.82-3.95(4H,m),4.05-4.30(4H,m),4.70(1H,m),5.6(1H,m),7.09(1H,s),7.39(1H,s),7.61(1H,t,J=7.6Hz),8.05(1H,d,J=7.6 Hz),9.31(1H,d,J=7.6 Hz),9.35(1H,brs),13.0(1H,brs).

mass:549(M+1)⁺.

Working Example 31

Synthesis of the Compound of the Following Formula [31]:

According to a method similar to the procedure described in WorkingExample 3-(1), the above benzoisothiazolone derivative (313 mg) wasobtained as a pale yellow solid from the carboxylic acid derivative (576mg, 1.00 mmol) obtained in Working Example 28-(1).

The benzoisothiazolone derivative (278 mg, 520 μmol) obtained in theabove (1) was dissolved in methylene chloride (5 mL), and to thesolution were added triethylamine (220 μL, 1.56 mmol) andmethanesulfonyl chloride (60 μL, 780 μmol) with stirring at 0° C. Themixture was stirred at the same temperature for 1 hour. 1N aqueouspotassium hydrogensulfate was added the resulting reaction solution, andthe solution was stirred at room temperature for 30 minutes. Then, thereaction solution was extracted with chloroform. The organic layer waswashed with saturated brine, dried with anhydrous sodium sulfate, andfiltered. The filtrate was concentrated, and the resulting residue wasdried with a vacumpump, and dissolved in N,N-dimethylformamide (10 mL).After potassium carbonate (222 mg, 1.56 mmol) and(R)-3-hydroxypyrrolidine hydrochloride (200 mg, 1.56 mmol) were addedthereto, the mixture was heated with stirring at 70° C. for 4 hours. Tothis reaction solution was added 1N aqueous potassium hydrogensulfate,and the mixture was stirred at room temperature for 30 minutes, thenextracted with chloroform. The organic layer was washed with saturatedbrine, dried over anhydrous sodium sulfate, and filtered. The filtratewas concentrated, and the resulting residue was purified by a columnchromatography on silica gel to obtain the above amine derivative (114mg) as a pale yellow solid.

According to a method similar to the procedures described in WorkingExample 14-(12) to 14-(13), the above cyclic derivative (10 mg) wasobtained as a yellow oil from the amine derivative (13 mg, 21 μmol)obtained in the above (2).

According to a method similar to the procedures described in WorkingExamples 14-(14) and 11-(18), the hydrochloride (13 mg) of the objectivecompound [31] was obtained as a yellow solid from the cyclic derivative(12 mg, 21 mmol) obtained in the above (3) and piperidine.

Spectral data of the compound of the above formula [31] are shown below.

¹H-NMR(DMSO-d₆)δ:1.20-2.10(8H,m),2.20-3.50(8H,m),3.50-4.40(6H,m),5.50(1H,m),6.98-7.10(1H,m),7.50-7.80(2H,m),7.98-8.10(1H,m),9.28(1H,d,J=8.2Hz).

mass:504(M+1)⁺.

Working Example 32

Synthesis of the Compound of the Following Formula [32]:

According to a method similar to the procedures described in WorkingExamples 14-(14) and 11-(18), the hydrochloride (88 mg) of the objectivecompound [32] was obtained as a yellow solid from the cyclic derivative(143 mg, 317 μmol) obtained in Working Example 31-(3) and morpholine.

Spectral data of the compound of the above formula [32] are shown below.

¹H-NMR(DMSO-d₆)δ:1.80-2.60(6H,m),2.80-3.50(3H,m),3.50-4.30(10H,m),4.30-4.50(1H,m)5.50(1H,m),6.90-7.05(1H,m),7.40-7.80(2H,m),7.90-8.10(1H,m),9.20-9.30(1H,m).

mass:506(M+1)⁺.

Working Example 33

Synthesis of the Compound of the Following Formula [33]:

According to a method similar to the procedures as Working Examples31-(2) and 32-(3), the above cyclic derivative was obtained from thebenzoisothiazolone derivative obtained in Working Example 31-(1) and(S)-3-hydroxypyrrolidine hydrochloride.

According to a method similar to the procedures described in WorkingExamples 14-(14) and 11-(18), the trifluoroacetate (37 mg) of theobjective compound [33] as a diastereomer mixture was obtained as ayellow solid from the cyclic derivative (68 mg, 151 μmol) obtained inthe above (1) and the racemic amine derivative [A-22].

Spectral data of the compound of the above formula [33] are shown below.

¹H-NMR(DMSO-d₆)6:0.80-1.20(2H,m),1.40-2.60(8H,m),2.60-3.80(8H,m),3.20(3H,s),4.10-4.50(3H,m)5.30(1H,m),6.90-7.02(1H,m),7.10-7.20(1H,m),7.58(1H,m),8.01-8.02(1H,m),9.30(1H,m),9.48(1H,brs),13.0(1H,brs).

mass:534(M+1)⁺.

Working Example 34

Synthesis of the Compound of the Following Formula [34]:

According to a method similar to the procedures described in WorkingExamples 14-(14) and 11-(18), the trifluoroacetate (27 mg) of theobjective compound [34] was obtained as a yellow solid from the cyclicderivative (60 mg, 133 μmol) obtained in Working Example 31-(3) and theracemic amine derivative [A-23].

Spectral data of the compound of the above formula [34] are shown below.

¹H-NMR(DMSO-d₆)δ:1.50-2.09(5H,m),2.25-2.33(1H,m),2.71-3.22(3H,m),3.24-3.28(3H,m),3.31-3.43(3H,m),3.66-3.73(2H,m),3.80-4.00(2H,m),4.05-4.50(5H,m),5.31-5.43(1H,m),7.00-7.29(1H,m),7.55-7.75(2H,m),8.03-8.15(1H,m),9.30-9.35(1H,m),9.65(1H,brs),12.9-13.2(1H,m).

mass:534(M+1)⁺.

Working Example 35

Synthesis of the Compound of the Following Formula [35]:

According to a method similar to the procedures described in WorkingExamples 14-(14) and 11-(18), the trifluoroacetate (25 mg) of theobjective compound [35] was obtained as a yellow solid from the cyclicderivative (60 mg, 133 μmol) obtained in Working Example 31-(3) and theamine derivative [A-24].

Spectral data of the compound of the above formula [35] are shown below.

¹H-NMR(DMSO-d₆)δ:1.17-1.96(5H,m),2.12-2.40(1H,m),2.72-3.23(3H,m),3.23-3.28(3H,m),3.38-3.60(5H,m),3.60-3.74(2H,m),4.12-4.43(5H,m),5.35-5.41(1H,m),7.06-7.30(1H,m),7.50-7.80(2H,m),8.03-8.06(1H,m),9.31-9.34(1H,m),9.64 (1H,brs),12.9-13.0(1H,m).

mass:534(M+1)⁺.

Working Example 36

Synthesis of the Compound of the Following Formula [36]:

According to a method similar to the procedures described in WorkingExamples 14-(14) and 11-(18), the trifluoroacetate (41 mg) of theobjective compound [36] was obtained as a yellow solid from the cyclicderivative (70 mg, 150 μmol) obtained in Working Example 31-(3) and theamine derivative [A-27].

Spectral data of the compound of the above formula [36] are shown below.

¹H-NMR(DMSO-d₆)δ:1.30-1.80(7H,m),2.06-2.93(7H,m),3.06-3.87(10H,m),4.25-4.39(2H,m),5.35(1H,brs),7.02(1H,s),7.19(1H,s),7.57(1H,t,J=7.2Hz),8.03(1H,d,J=7.2 Hz),9.30(1H,d,J=7.2 Hz),12.9(1H,s).

mass:548(M+1)⁺.

Working Example 37

Synthesis of the Compound of the Following Formula [37]:

According to a method similar to the procedures described in WorkingExamples 14-(14) and 11-(18), the trifluoroacetate (41 mg) of theobjective derivative [37] was obtained as a yellow solid from the cyclicderivative (70 mg, 150 mmol) obtained in Working Example 31-(3) and theamine derivative [A-28].

Spectral data of the compound of the above formula [37] are shown below.

¹H-NMR(DMSO-d₆)δ:1.30-1.80(7H,m),2.06-2.93(7H,m),3.06-3.87(10H,m),4.25-4.39(2H,m),5.35(1H,brs),7.02(1H,s),7.19(1H,s),7.57(1H,tJ=7.2Hz),8.03(1H,d,J=7.2 Hz),9.30(1H,d,J=7.2 Hz),12.9 (1H,s).

mass:548(M+1)⁺.

Working Example 38

Synthesis of the Compound of the Following Formula [38]:

According to a method similar to the procedure described in WorkingExample 1-(2), the above amide derivative (250 mg) was obtained as anorange solid from the carboxylic acid derivative (200 mg, 340 μmol)obtained in Working Example 28-(1) and the amine derivative [A-16].

The amide derivative (190 mg, 0.26 mmol) obtained in the above (1) wasdissolved in methylene chloride (5.0 mL) under a nitrogen atmosphere,and N-methylpyrrolidine (104 μL, 1.04 mmol) was added thereto. Thereaction solution was cooled to −78° C., and a solution of sulfurylchloride in methylene chloride (1.04 mL, 0.5M, 0.52 mmol) was addeddropwise at −78° C. The reaction solution was stirred at the sametemperature for 1 hour. The resulting reaction solution was poured intoan aqueous solution of sodium sulfite and potassium carbonate, and thenextracted with chloroform twice. The organic layer was dried overanhydrous sodium sulfate, filtered, and concentrated. The resultingresidue was purified by a column chromatography on silica gel to obtainthe above benzoisothiazolone derivative (169 mg) as a yellow solid.

According to a method similar to the procedures described in WorkingExamples 11-(9), and 14-(12) to 14-(13), the above cyclic derivative (46mg) was obtained as a yellow solid from the benzoisothiazolonederivative (225 mg, 340 μmol) obtained in the above (2).

According to a method similar to the procedures described in WorkingExamples 14-(14) and 11-(18), the trifluoroacetate. (41 mg) of theobjective compound [38] was obtained as a yellow solid from the cyclicderivative (70 mg, 150 μmol) obtained in the above (3) and the aminederivative [A-23].

Spectral data of the compound of the above formula [38] are shown below.

¹H-NMR(DMSO-d₆)δ:1.23-2.25(9H,m),2.90-3.14(2H,m),3.25(3H,s),3.28-3.38(2H,m),3.43-3.58(2H,m),3.63-3.78(2H,m),4.10-5.10(6H,m),5.43(1H,brs),7.02-7.14(1H,m),7.32-7.46(1H,m),7.66-7.75(1H,m),8.08-8.18(1H,m),9.46-9.52(1H,m),12.9(1H,s).

mass:548(M+1)⁺.

Working Example 39

Synthesis of the Compound of the Following Formula [39]:

According to a method similar to the procedures described in WorkingExamples 14-(14) and 11-(18), the hydrochloride (14 mg) of the objectivecompound [39] was obtained as a yellow solid from the cyclic derivative(46 mg, 100 μmol) obtained in Working Example 38-(3) and morpholine.

Spectral data of the compound of the above formula [39] are shown below.

¹H-NMR(DMSO-d₆)δ:2.08-2.33(4H,m) 3.03-3.80(12H,m),3.84-4.03.(4H,m),4.20-4.55(2H,m),5.58(1H,brs),7.03(1H,s),7.66(1H,t,J=8.0Hz),7.89(1H,s),8.07(1H,d,J=8.0 Hz),9.42(1H,d,J=8.0 Hz),12.9(1H,s).

mass:520(M+1)⁺.

Working Example 40

Synthesis of the Compound of the Following Formula [40]:

According to a method similar to the procedures of Working Examples1-(2) to 1-(5), the above racemic cyclic derivative (2.01 g) wasobtained as a yellow solid from the carboxylic acid derivative (6.61 g,8.88 mmol) prepared in Working Example 14-(2) and a racemate of5-amino-1-hexanol synthesized by referring to a method similar to themethod described in J. Med. Chem., 25(8) 964 (1982).

According to a method similar to the procedures described in WorkingExamples 14-(5) to 14-(6), the above racemic carboxylic acid derivative(464 mg) was obtained as an orange solid from the racemic cyclicderivative (529 mg, 880 μmol) obtained in the above (1).

The racemic carboxylic acid derivative (464 mg, 820 μmol) obtained inthe above (2) was dissolved in tetrahydrofuran (50 mL) andN,N-dimethylformamide (14 mL), and then 1,1′-carbonylbis-1H-imidazole(199 mg, 1.23 mmol) was added thereto. The reaction solution was stirredat room temperature for 11 hours, and then lithium tetrahydroborate(35.6 mg, 1.64 mmol) was added. Lithium tetrahydroborate (35.6 mg, 1.64mmol) was added to the resulting reaction solution, and the mixture wasstirred at room temperature for 30 minutes. After that, lithiumtetrahydroborate (35.6 mg, 1.64 mmol) was further added thereto, and themixture was stirred at room temperature for 30 minutes, and thenchloroform (50 mL) was added to the reaction solution. After addition ofsaturated aqueous ammonium chloride (30 mL), the solution was extractedwith chloroform. The organic layer was washed with saturated brine, anddried over anhydrous magnesium sulfate, and filtered. The filtrate wasconcentrated in vacuo, and the resulting residue was evaporatedazeotropically using toluene. The resulting residue was dissolved inmethylene chloride (30 mL) and chloroform (30 mL). After manganesedioxide (214 mg, 2.45 mmol) was added to this solution, the mixture wasstirred at room temperature for 2 hours. The resulting reaction solutionwas filtered through a Celite pad, and then concentrated in vacuo. Theresidue was purified by a column chromatography on silica gel to obtainthe above racemic benzyl alcohol derivative (298 mg) as a yellowishbrown solid.

The racemic benzyl alcohol derivative (298 mg, 540 μmol) obtained in theabove (3) was dissolved in chloroform (20 mL), and manganese dioxide(468 mg, 5.38 mmol) was added thereto. The mixture was stirred at roomtemperature for 11 hours. The resulting reaction solution was filteredthrough a Celite pad, and the filtrate was concentrated in vacuo. Theresulting residue was purified by a thin layer chromatography to obtainthe above-racemic aldehyde (175 mg) as a yellowish brown solid.

To chloroform solution (20 mL) containing the racemic aldehydederivative (100 mg, 180 μmol) obtained in the above (4) and pyrrolidine(121 μL, 1.45 mmol) was added methanol solution (2.42 mL) containingzinc chloride (50 mg, 364 μmol) and sodium cyanotrihydroborate (47 mg,726 μmol), and the mixture was stirred at room temperature for 12 hours.The resulting reaction solution was concentrated, and the resultingresidue was diluted with chloroform, and washed with water and saturatedbrine. The organic layer was dried over anhydrous magnesium sulfate, andfiltered. The filtrate was concentrated in vacuo, and the resultingresidue was purified by a thin layer chromatography to obtain the aboveracemic benzylamine derivative (70 mg) as a yellowish brown solid.

According to a method similar to the procedure described in WorkingExample 1-(6), the hydrochloride (49 mg) of the objective compound [40]as a racemate was obtained as a yellow solid from the racemicbenzylamine derivative (70 mg, 120 μmol) obtained in the above (5).

Spectral data of the compound of the above formula [40] are shown below.

¹H-NMR(DMSO-d₆)δ:1.24(3H,d,J=6.6Hz),1.80-2.08(10H,m),3.05-3.12(2H,m),3.38-3.45(2H,m),4.14-4.21(1H,m),4.43-4.52(3H,m),4.58-4.63(1H,m),7.06(1H,s),7.39(1H,s),7.65(1H,t,J=7.8Hz),8.06(1H,d,J=7.8 Hz),9.45(1H,d,J=7.8 Hz),10.8(1H,brs),13.0(1H,s).

mass:477(M+1)⁺.

Working Example 41

Synthesis of the Compound of the Following Formula [41]:

According to a method similar to the procedures described in WorkingExamples 40-(5) to 40-(6), the hydrochloride (12 mg) of the objectivecompound [41] as a racemate was obtained as a yellowish brown solid fromthe racemic aldehyde derivative (20 mg, 36 μmol) obtained in WorkingExample 40-(4) and morpholine.

Spectral data of the compound of the above formula [41] are shown below.

¹H-NMR(DMSO-d₆)6:1.22(3H,d,J=6.3Hz),1.76-1.97(4H,m),2.24-2.43(2H,m),3.11-3.29(4H,m),3.81-3.95(4H,m),4.11-4.17(1H,m),4.41-4.47(3H,m),4.56-4.59(1H,m),7.02(1H,s),7.49(1H,s),7.60(1H,t,J=7.8Hz),8.01(1H,d,J=7.8 Hz),9.44(1H,d,J=7.8 Hz),11.5(1H,b rs),13.0(1H,s).

mass:493(M+1)⁺.

Working Example 42

Synthesis of the Compound of the Following Formula [42]:

According to a method similar to the procedures described in WorkingExamples 14-(14) and 1-(6), the hydrochloride (40 mg) of the objectivecompound [42] as a racemate was obtained as a yellowish brown solid fromthe racemic benzyl alcohol derivative (177 mg, 140 μmol) obtained inWorking Example 40-(3) and 4-methylpiperidine.

Spectral data of the compound of the above formula [42] are shown below.

¹H-NMR(DMSO-d₆)6:0.91(3H,d,J=6.3 Hz),1.24(3H,d,J=6.9Hz),1.38-1.64(4H,m),1.74-2.01(5H,m),2.25-2.40(2H,m),2.88-3.00(2H,m),3.11-3.18(1H,m),3.25-3.45(1H,m),4.15-4.22(1H,m),4.33-4.38(2H,m),4.45-4.51(1H,m),4.58-4.64(1H,m),7.04(1H,s),7.34(1H,s),7.66(1H,t,J=7.8Hz),8.07(1H,d,J=7.8 Hz),9.45(1H,d,J=7.8 Hz),10.1(1H,brs),13.1(1H,s).

mass:505(M+1)⁺.

Working Example 43

Synthesis of the Compound of the Following Formula [43]:

The racemic cyclic derivative (143 mg, 51 μmol) obtained in WorkingExample 40-(1) was dissolved in toluene (1.5 mL), and to this solutionwere added N-methylpiperazine (136 μL, 122 μmol),(R)-(+)-2,2′-bis(di-4-tolylphosphino)-1,1′-binaphthyl (9.5 mg, 15 μmol),tris(dibenzylideneacetone) dipalladium(0)-chloroform adduct (5.3 mg, 5μmol) and sodium t-butoxide (9.8 mg, 102 μmol). The mixture was stirredat 80° C. for 5 hours. The resulting reaction solution was cooled downto room temperature, extracted with chloroform, and the extract waswashed successively with water and saturated brine. The organic layerwas dried over anhydrous magnesium sulfate, filtered, and concentratedin vacuo. The resulting residue was purified by a thin layerchromatography to obtain the above racemic 6-piperazine derivative (30mg) as a yellowish brown liquid.

According to a method similar to the procedure described in WorkingExample 1-(6), the hydrochloride (11 mg) of the objective compound [43]as a racemate was obtained as a yellowish brown solid from the racemic6-piperazine derivative (30 mg, 48 μmol) obtained in the above (1).

Spectral data of the compound of the above formula [43] are shown below.

¹H-NMR(DMSO-d₆)δ:1.22(3H,d,J=6.6Hz),1.78-1.90(4H,m),2.23-2.39(2H,m),2.83(3H,d,J=3.9Hz),3.14-3.39(6H,m),3.96-4.11(3H,m),4.38-4.44(1H,m),4.53-4.58(1H,m),6.31(1H,s),6.68(1H,s),7.57(1H,t,J=7.8 Hz),7.94(1H,d,J=7.8 Hz),9.27(1H,d,J=7.8 Hz),10.9.(1H,brs),12.5(1H,s).

mass:492(M+1)⁺.

Working Example 44

Synthesis of the Compound of the Following Formula [44]:

According to a method similar to the procedure described in WorkingExample 11-(4), the above racemic vinyl derivative (60 mg) was obtainedas an orange solid from the racemic cyclic derivative (116 mg, 139 μmol)obtained in Working Example 40-(1).

Pyrrolidine (4 mL) was added to the racemic vinyl derivative (23.5 mg,43 μmol) obtained in the above (1), and the mixture was heated in asealed tube at 120° C. for 15 hours. The resulting reaction solution wasconcentrated in vacuo, and the resulting residue was diluted withchloroform, and washed with water and saturated brine. The organic layerwas dried over anhydrous magnesium sulfate, and filtered, andconcentrated in vacuo. The resulting residue was purified by a thinlayer chromatography to obtain the above racemic pyrrolidinylethylderivative (6.3 mg) as a yellowish brown solid.

According to a method similar to the procedure described in WorkingExample 1-(6), the hydrochloride (2.9 mg) of the objective compound [44]as a racemate was obtained as a yellowish brown solid from the racemicpyrrolidinylethyl derivative (6.3 mg, 10 μmol) obtained in the above(2).

Spectral data of the compound of the above formula [44] are shown below.

¹H-NMR(DMSO-d₆)δ:1.23(3H,d,J=6.3Hz),1.85-2.02(6H,m),2.26-2.62(4H,m),3.05-3.12(2H,m),3.25-3.59(6H,m),4.10-4.25(1H,m),4.40-4.48(1H,m),4.54-4.68(1H,m),6.84(1H,s),6.98(1H,s),7.63(1H,t,J=7.8Hz),8.03(1H,d,J=7.8 Hz),9.41(1H,d,J=7.8 Hz),10.5 (1H,brs),12.9(1H,s).

mass:491(M+1)⁺.

Working Example 45

Synthesis of the Compound of the Following Formula [45]:

The cyclic derivative (18.9 mg, 42 μmol) obtained in Working Example31-(3) and methyl iodide (4 μL, 63 μmol) were dissolved inN,N-dimethylformamide (10 mL). Sodium hydride (2.0 mg, 60% dispersion inoil, 50 μmol) was added to this solution in an ice-bath, and thesolution was stirred at the same temperature for 2 hours. After methyliodide (12 μL, 189 μmol) and sodium hydride (6.0 mg, 60% dispersion inoil, 150 μmol) were further added thereto in an ice-bath, the solutionwas stirred at room temperature for 7.5 hours. After saturated aqueousammonium chloride was added to the resulting reaction solution, it wasextracted with chloroform. The organic layer was washed with water andsaturated brine, dried over anhydrous magnesium sulfate, and filtered.The filtrate was concentrated in vacuo, and the residue was evaporatedazeotropically using toluene, and the resulting residue was purified bya thin layer chromatography to obtain the above methoxymethyl derivative(15.6 mg) as a yellowish brown oil.

According to a method similar to the procedure described in WorkingExample 11-(18), the hydrochloride (6.9 mg) of the objective compound[45] was obtained as a yellowish brown solid from the methoxymethylderivative (15.6 mg, 33 μmol) obtained in the above (1).

Spectral data of the compound of the above formula [45] are shown below.

¹H-NMR(DMSO-d₆)6:1.93-2.06(1H,m),2.21-2.30(1H,m),2.72-3.16(4H,m),3.25-3.45(4H,m),3.59-4.10(2H,m),4.10-4.15(1H,m),4.46-4.55(2H,m),5.33-5.43(1H,m),6.78-7.04(2H,m),7.54-7.71(1H,m),8.00-8.12(1H,m),9.31 (1H,brs),12.8(1H,s).

mass:451(M+1)⁺.

Working Example 46

Synthesis of the Compound of the Following Formula [46]:

According to a method similar to the procedures described in WorkingExamples 11-(10) to 11-(12), the above 3-indazolinone derivative (737mg) was obtained as an orange solid from the carboxylic acid derivative(944 mg, 2.0 mmol) obtained in Working Example 11-(9) and the hydrazinederivative [A-18].

According to a method similar to the procedure described in WorkingExample 11-(9), the above alcohol derivative (531 mg) was obtained as anorange solid from the 3-indazolinone derivative (737 mg) obtained in theabove (1).

According to a method similar to the procedure described in WorkingExamples 11-(14) to 11-(18), the hydrochloride (95 mg) of the objectivecompound [46] was obtained as a purple solid from the alcohol derivative(531 mg, 940 pimol) obtained in the above (2) and piperidine.

Spectral data of the compound of the above formula [46] are shown below.

¹H-NMR(DMSO-d₆)δ:1.30-1.44(1H,m),1.48(3H,d,J=6.0Hz),1.65-2.00(10H,m),2.05-2.15(1H,m),2.82-2.96(2H,m),3.20-3.28(1H,m),3.30-3.38(1H,m),3.86-3.98(1H,m),4.12-4.22(1H,m),4.24-4.34(1H,m),4.36-4.44(1H,m),4.76-4.88(1H,m),6.95(1H,s),7.17(1H,t,J=8.0Hz),7.45(1H,s),7.83(1H,d,J=8.0 Hz),9.22(1H,d,J=8.0Hz),10.8-10.9(1H,brs),11.4(1H,s),12.8(1H,s).

mass:474(M+1)⁺.

Working Example 47

Synthesis of the Compound of the Following Formula [47]:

According to a method similar to the procedures as Working Example 46,the hydrochloride of the objective compound [47] was obtained from thecarboxylic acid derivative obtained in Working Example 11-(9) and thehydrazine derivative [A-19].

Spectral data of the compound of the above formula [47] are shown below.

¹H-NMR(DMSO-d₆)δ:1.30-1.44(1H,m),1.48(3H,d,J=6.0Hz),1.65-2.00(10H,m),2.05-2.15(1H,m),2.82-2.96(2H,m),3.20-3.28(1H,m),3.30-3.38(1H,m),3.86-3.98(1H,m),4.12-4.22(1H,m),4.24-4.34(1H,m),4.36-4.44(1H,m),4.76-4.88(1H,m),6.95(1H,s),7.17(1H,t,J=8.0Hz),7.45(1H,s),7.83(1H,d,J=8.0 Hz),9.22(1H,d,J=8.0Hz),10.8-10.9(1H,brs),11.4(1H,s),12.8(1H,s).

mass:474(M+1)⁺.

Working Example 48

Synthesis of the Compound of the Following Formula [48]:

Triethylamine (167 μL, 1.20 mmol) and 2-chloro-1,3-dimethylimidazoliniumchloride (102 mg, 602 μL) were added to chloroform solution (5 mL) ofthe carboxylic acid derivative (200 mg, 367 μmol) obtained by referenceto Working Example 110-2) described in WO02/02550, and the mixture wasstirred for 10 minutes. After that, to this solution was added thehydrazine derivative [A-20] (275 mg, 602 μL), and the mixture wasstirred at room temperature for 2 hours. The resulting reaction solutionwas purified by a thin layer chromatography to obtain the abovehydrazide derivative (213 mg) as a yellow oil.

10% hydrochloric acid/methanol (2 mL) was added to the hydrazidederivative (50 mg, 50.9 μmol) obtained in the above (1), and the mixturewas stirred at room temperature for 15 hours. The resulting reactionsolution was concentrated, and the resulting residue was purified by athin layer chromatography to obtain the above de-Boc derivative (28 mg)as a yellow oil.

According to a method similar to the procedure described in WorkingExample 11-(12), the above 3-indazolinone derivative (14 mg, 27 μmol)was obtained as an orange solid from the de-Boc derivative (28 mg)obtained in the above (2).

According to a method similar to the procedures described in WorkingExamples 1-(5) tol-(6), the objective compound [48](8 mg) was obtainedas an orange solid from the 3-indazolinone derivative (14 mg, 27 μmol)obtained in the above (3).

Spectral data of the compound of the above formula [48] are shown below.

¹H-NMR(DMSO-d₆)δ:1.73-2.10(6H,m),4.00-4.11(2H,m),4.15-4.23(2H,m),6.84-6.90(2H,m),7.17(1H,t,J=7.7Hz),7.45(1H,t,J=8.2 Hz),7.83(1H,d,J=7.7 Hz),9.24(1H,d,J=7.7Hz),11.6(1H,s),12.6(1H,b rs).

mass:363(M+1)⁺

Working Example 49

Synthesis of the Compound of the Following Formula [49]:

According to a method similar to the procedure described in WorkingExample 11-(9), the above carboxylic acid derivative (8.42 g) wasobtained as a pale yellow solid from the protected derivative (10 g)with SEM obtained in Working Example 14-(1).

According to a method similar to the procedures including the steps ofup to the macrocyclization described in Working Examples 48-(1) to48-(4), the above racemic cyclic derivative (6.9 mg) was obtained as ayellowish brown solid from the carboxylic acid derivative (15.6 mg, 33μmol) obtained in the above (1) and the racemic hydrazine derivative[A-21].

According to a method similar to the procedure described in WorkingExample 14-(5) to 14-(6), the above racemic carboxylic acid derivative(188 mg) was obtained as an orange solid from the racemic cyclicderivative (192 mg, 326 μmol) obtained in the above (2).

The racemic carboxylic acid derivative (188 mg, 340 μmol) obtained inthe above (3) was dissolved in tetrahydrofuran (10 mL), and to thesolution was added 1,1′-carbonylbis-1H-imidazole (83 mg, 510 μmol). Themixture was stirred at room temperature for 17 hours. To the resultingreaction solution were slowly added sodium tetrahydroborate (26 mg, 680μmol) and water (10 mL), and the mixture was stirred at room temperaturefor 20 minutes. After saturated aqueous ammonium chloride solution wasadded to this reaction solution, the mixture was extracted withchloroform. The organic layer was washed with saturated brine, driedover anhydrous magnesium sulfate, filtered, and concentrated in vacuo.The resulting residue was purified by a thin layer chromatography. Theresulting compound was dissolved in methylene chloride (6 mL), andmanganese dioxide (133 mg, 1.53 mmol) was added thereto. The mixture wasstirred at room temperature for 18 hours. The resulting reactionsolution was filtered through a Celite pad and the filtrate wasconcentrated in vacuo. The resulting residue was purified by a thinlayer chromatography to obtain the above racemic aldehyde derivative (44mg) as an orange solid.

According to a method similar to the procedures described in WorkingExamples 40-(5) to 40-(6), the hydrochloride (12 mg) of the racemicobjective compound [49] as a racemate was obtained as a deep purplesolid from the racemic aldehyde derivative (22 mg, 41 μmol) obtained inthe above(4) and pyrrolidine.

Spectral data of the compound of the above formula [49] are shown below.

¹H-NMR(DMSO-d₆)δ:1.05(3H,d,J=5.7Hz),1.71-1.85(6H,m),1.92-2.17(4H,m),2.96-3.05(2H,m),3.25-3.45(2H,m),4.08-4.15(1H,m),4.31-4.39(3H,m),4.48-4.54(1H,m),6.95(1H,s),7.16(1H,t,J=7.8Hz),7.35(1H,s),7.75(1H,d,J=7.8 Hz),9.02(1H,d,J=7.8 Hz),10.5(1H,brs),10.9(1H,s),12.8(1H,s).

mass:460(M+1)⁺.

Working Example 50

Synthesis of the Compound of the Following Formula [50]:

According to a method similar to the procedures described in WorkingExample 40-(5) to 40-(6), the hydrochloride (79 mg) of the racemicobjective compound [50] as a racemate was obtained as a deep green solidfrom the racemic aldehyde derivative (102 mg, 169 μmol) obtained inWorking Example 49-(4) and piperidine.

Spectral data of the compound of the above formula [50] are shown below.

¹H-NMR(DMSO-d₆)δ:1.14(3H,d,J=6.0Hz),1.75-1.86(10H,m),2.05-2.19(2H,m),2.88-2.95(2H,m),3.25-3.56(2H,m),4.17-4.24(1H,m),4.32-4.46(3H,m),4.56-4.73(1H,m),7.04(1H,s),7.25(1H,t,J=7.8Hz),7.46(1H,s),7.85(1H,d,J=7.8 Hz),9.10(1H,d,J=7.8 Hz),10.2(1H,brs),11.0(1H,s),12.9(1H,s).

mass:474(M+1)⁺.

Working Example 51

Synthesis of the Compound of the Following Formula [51]:

According to a method similar to the procedures up to the step of themacrocyclization described in Working Examples 48-(1) to 48-(4), and14-(5) to 14-(6), the above carboxylic acid derivative (580 mg) wasobtained as a yellowish brown solid from the carboxylic acidderivative(2.48 g, 3.87 mmol) obtained in Working Example 49-(1).

The carboxylic acid derivative (580 mg, 1.08 mmol) obtained in the above(1) was dissolved in tetrahydrofuran (60 mL) and N,N-dimethylformamide(60 mL), and to this solution was added 1,1′-carbonylbis-1H-imidazole(262 mg, 1.62 mmol). The mixture was stirred at 60° C. for 30 minutes,and further at room temperature for 11 hours. Lithium tetrahydroborate(47 mg, 2.16 mmol) was added to the resulting reaction solution, and itwas stirred at room temperature for 30 minutes. After that, lithiumtetrahydroborate (500 mg, 23 mmol) was further added to this solution,and the mixture was stirred at room temperature for 1 hour, followed byaddition of chloroform (100 mL). Then, saturated aqueous ammoniumchloride solution (50 mL) was added to this solution, and the mixturewas extracted with chloroform. The organic layer was washed withsaturated brine, dried over anhydrous magnesium sulfate, and filtered.The filtrate was concentrated in vacuo and evaporated azeotropicallyusing toluene. The resulting residue was dissolved in chloroform (100mL), and then manganese dioxide (282 mg, 3.24 mmol) was added to thesolution. The mixture was stirred at room temperature for 1 hour. Theresulting reaction solution was filtered through a Celite pad andconcentrated in vacuo. The resulting residue was purified by a columnchromatography on silica gel to obtain the above benzyl alcoholderivative (320 mg) as an orange liquid.

According to a method similar to the procedures described in WorkingExamples 11-(17) and 1-(6), the hydrochloride (55 mg) of the objectivecompound [51] was obtained as a deep purple solid from the benzylalcohol derivative (88 mg, 168 μmol) obtained in the above (2) andpiperidine.

Spectral data of the compound of the above formula [51] are shown below.

¹H-NMR(DMSO-d₆)δ:1.35-1.40(1H,m),1.66-2.26(11H,m),2.88-2.94(2H,m),3.25-3.45(2H,m),4.04-4.10(2H,m),4.24-4.30(2H,m),4.31-4.37(2H,m),7.00(1H,s),7.21(1H,t,J=7.8Hz),7.30(1H,s),7.87(1H,d,J=7.8 Hz),9.26(1H,d,J=7.8Hz),10.3(1H,brs),11.6(1H,s),12.9(1H,s).

mass:460(M+1)⁺.

Working Example 52

Synthesis of the Compound of the Following Formula [52]:

According to a method similar to the procedures described in WorkingExamples 11-(17) and 1-(6), the hydrochloride (28 mg) of the objectivecompound [52] was obtained as a deep green solid from the benzyl alcoholderivative (66 mg, 127 μmol) obtained in the above (2) and piperidine.

in Working Example 51-(2) and pyrrolidine.

Spectral data of the compound of the above formula [52] are shown below.

¹H-NMR(DMSO-d₆)δ: 1.83-1.90(6H,m)1.92-2.03(4H,m),3.03-3.10(2H,m),3.36-3.44(2H,m),4.05-4.09(2H,m),4.22-4.26(2H,m),4.41-4.43(2H,m),7.00(1H,s),7.19(1H,t,J=7.8Hz),7.33(1H,s),7.85(1H,d,J=7.8 Hz),9.25(1H,d,J=7.8 Hz),11.0(1H,brs),11.6(1H,s),12.9(1H,s).

mass:446(M+1)⁺.

Working Example 53

Synthesis of the Compound of the Following Formula [53]:

According to a method similar to the procedures described in WorkingExamples 11-(17) and 1-(6), the hydrochloride (7 mg) of the objectivecompound [53] was obtained as a yellow green solid from the benzylalcohol derivative (10 mg, 19 μmol) obtained in Working Example 51-(2)and morpholine.

Spectral data of the compound of the above formula [53] are shown below.

¹H-NMR(DMSO-d₆)δ:1.81-1.95(4H,m),2.04-2.26(2H,m),3.11-3.21(4H,m),3.69-3.81(2H,m),3.91-3.99(2H,m),4.05-4.10(2H,m),4.26-4.31(2H,m),4.41-4.46(2H,m),7.02(1H,s),7.21(1H,t,J=7.8Hz),7.26(1H,s),7.88(1H,d,J=7.8 Hz),9.28(1H,d,J=7.8 Hz),10.7(1H,brs),11.6(1H,s),12.9(1H,s).

mass:462(M+1)⁺.

Working Example 54

Synthesis of the Compound of the Following Formula [54]:

According to a method similar to the procedures described in WorkingExamples 11-(17) and 1-(6), the hydrochloride (6 mg) of the racemicobjective compound [53] as a racemate was obtained as a deep green solidfrom the benzyl alcohol derivative (10 mg, 19 μmol) obtained in WorkingExample 51-(2) and a racemic 2-methylpiperidine.

Spectral data of the compound of the above formula [54] are shown below.

¹H-NMR(DMSO-d₆)6:1.36-1.50(3H,m), 1.66-1.92(10H,m),1.94-2.08(2H,m),2.71-2.82(1H,m),3.01-3.11(2H,m),4.03-4.13(3H,m),4.23-4.35(2H,m),4.71-4.77(1H,m),6.99-7.18(1H,m),7.21(1H,t,J=7.8Hz),7.31-7.40(1H,m),7.87(1H,d,J=7.8 Hz),9.26(1H,d,J=7.8Hz),10.2(1H,brs),11.6(1H,s),12.9(1H,s).

mass:474(M+1)⁺.

Working Example 55

Synthesis of the Compound of the Following Formula [55]:

According to a method similar to the procedures described in WorkingExamples 11-(17) and 1-(6), the hydrochloride (7 mg) of the objectivecompound [55] as a racemate was obtained as a green solid from thebenzyl alcohol derivative (10 mg, 19 μmol) obtained in Example 51-(2)and a racemic 3-methylpiperidine.

Spectral data of the compound of the above formula [55] are shown below.

¹H-NMR(DMSO-d₆)δ:0.86(3H,d,J=6.6Hz),1.75-2.12(11H,m),3.20-3.40(4H,m),4.04-4.10(2H,m),4.25-4.28(2H,m),4.32-4.34(2H,m),6.99(1H,s),7.20(1H,t,J=7.8Hz),7.32(1H,s),7.87(1H,d,J=7.8 Hz), 9.26(1H,d,J=7.8 Hz),10.4(1H,brs),11.6(1H,s),12.9(1H,s).

mass:474(M+1)⁺.

Working Example 56

Synthesis of the Compound of the Following Formula [56]:

According to a method similar to the procedures described in WorkingExample 11-(17) and 1-(6), the hydrochloride (8 mg) of the objectivecompound [56] as a racemate was obtained as a yellow green solid fromthe benzyl alcohol derivative (10 mg, 19 μmol) obtained in WorkingExample 51-(2) and a racemic 3-methoxycarbonylpiperidine.

Spectral data of the compound of the above formula [56] are shown below.

¹H-NMR(DMSO-d₆)δ:1.17(3H,t,J=7.2Hz),1.44-1.49(1H,m),1.72-1.97(6H,m),2.01-2.12(3H,m),2.89-3.09(4H,m),3.50-3.58(1H,m),4.04-4.12(4H,m),4.25-4.31(2H,m),4.40-4.44(2H,m),7.01(1H,s),7.22(1H,t,J=7.8Hz),7.24(1H,s),7.89(1H,d,J=7.8 Hz),9.29(1H,d,J=7.8 Hz),10.3(1H,brs),11.6(1H,s),12.9(1H,s).

mass:532(M+1)⁺.

Working Example 57

Synthesis of the Compound of the Following Formula [57]:

According to a method similar to the procedures described in WorkingExamples 11-(17) and 1-(6), the hydrochloride (6 mg) of the objectivecompound [57] was obtained as a deep green solid from the benzyl alcoholderivative (10 mg, 19 μmol) obtained in Working Example 51-(2) and(S)-2-methoxymethylpyrrolidine.

Spectral data of the compound of the above formula [57] are shown below.

¹H-NMR(DMSO-d₆)δ:1.67-2.07(9H,m),2.12-2.25(1H,m),3.06-3.28(2H,m),3.32(3H,s),3.66-3.92(3H,m),3.95-4.10(2H,m),4.11-4.34(3H,m),4.57-4.63(1H,m),6.97(1H,s),7.16(1H,t,J=7.8Hz),7.29-7.69(1H,m),7.83(1H,d,J=7.8 Hz),9.21(1H,d,J=7.8 Hz),10.8(1H,brs),11.5(1H,s),12.8(1H,s).

mass:490(M+1)⁺.

Working Example 58

Synthesis of the Compound of the Following Formula [58]:

According to a method similar to the procedures described in WorkingExamples 11-(17) and 1-(6), the hydrochloride (9 mg) of the objectivecompound [58] was obtained as a deep green solid from the benzyl alcoholderivative (10 mg, 19 μmol) obtained in Working Example 51-(2) and(R)-2-methoxymethylpyrrolidine.

Spectral data of the compound of the above formula [58] are shown below.

¹H-NMR(DMSO-d₆)δ: 1.68-2.20(10H,m),3.12-3.19(2H,m),3.32(3H,s),3.61-3.83(3H,m),4.03-4.06(2H,m),4.22-4.34(3H,m),4.58-4.63(1H,m),7.00(1H,s),7.19(1H,t,J=7.8 Hz),7.29(1H,m),7.83(1H,d,J=7.8Hz),9.25(1H,d,J=7.8 Hz),10.6 (1H,brs),11.6(1H,s),12.9(1H,s).

mass:490(M+1)⁺.

Working Example 59

Synthesis of the Compound of the Following Formula [59]:

According to a method similar to the procedures described in WorkingExamples 11-(17) and 1-(6), the hydrochloride (8 mg) of the objectivecompound [59] was obtained as a deep purple solid from the benzylalcohol derivative (10 mg, 19 μmol) obtained in Working Example 51-(2)and thiomorpholine.

Spectral data of the compound of the above formula [59] are shown below.

¹H-NMR(DMSO-d₆)δ:1.83-1.90(4H,m)2.03-2.08(2H,m),2.71-2.87(2H,m),3.05-3.21(2H,m),3.40-3.45(2H,m),3.56-3.75(2H,m),4.05-4.11(2H,m),4.23-4.32(2H,m),4.40-4.49(2H,m),7.02(1H,s),7.21(1H,t,J=7.8Hz),7.29(1H,s),7.88(1H,d,J=7.8 Hz),9.27(1H,d,J=7.8 Hz),10.7(1H,brs),11.6(1H,s),12.9(1H,s).

mass:478(M+1)⁺.

Working Example 60

Synthesis of the Compound of the Following Formula [60]:

According to a method similar to the procedures described in WorkingExamples 11-(17) and 1-(6), the hydrochloride (6 mg) of the objectivecompound [60] was obtained as an ocher solid from the benzyl alcoholderivative (10 mg, 19 μmol) obtained in Working Example 51-(2) and theamine derivative [A-29].

Spectral data of the compound of the above formula [60] are shown below.

¹H-NMR(DMSO-d₆)δ:1.55-1.65(1H,m),1.81-1.98(5H,m),2.02-2.27(4H,m),2.95-3.22(5H,m),3.26(3H,s),4.05-4.11(2H,m),4.25-4.30(2H,m),4.35-4.42(2H,m),7.00-7.04(1H,m),7.21(1H,t,J=7.8Hz),7.27(1H,s),7.88(1H,d,J=7.8 Hz),9.28(1H,d,J=7.8 Hz),10.2(1H,brs),11.6(1H,s),12.9(1H,s).

mass:490(M+1)⁺.

Working Example 61

Synthesis of the Compound of the Following Formula [61]:

According to a method similar to the procedures described in WorkingExamples 11-(17) and 1-(6), the hydrochloride (8 mg) of the objectivecompound [61] as a racemate was obtained as a green solid from thebenzyl alcohol derivative (10 mg, 19 μmol) obtained in Working Example51-(2) and the racemic amine derivative [A-22].

Spectral data of the compound of the above formula [61] are shown below.

¹H-NMR(DMSO-d₆)δ:1.21-1.23(1H,m),1.38-1.56(1H,m),1.61-1.95(6H,m),2.01-2.10(2H,m),2.95-3.20(1H,m),3.20-3.56(5H,m),3.56-3.80(2H,m),4.02-4.10(2H,m),4.18-4.24(2H,m),4.24-4.41(2H,m),6.97-7.04(1H,m),7.15-7.40(2H,m),7.85-7.86(1H,m),9.24-9.25(1H,m),11.2(1H,brs),11.6(1H,s),12.8-12.9(1H,m).

mass:490(M+1)⁺.

Working Example 62

Synthesis of the Compound of the Following Formula [62]:

According to a method similar to the procedures described in WorkingExamples 11-(17) and 1-(6), the hydrochloride (7 mg) of the objectivecompound [62] as a racemate was obtained as a green solid from thebenzyl alcohol derivative (10 mg, 19 μmol) obtained in Working Example51-(2) and the racemic amine derivative [A-25].

Spectral data of the compound of the above formula [62] are shown below.

¹H-NMR(DMSO-d₆)δ:1.12-1.24(1H,m),1.66-1.74(1H,m),1.78-1.96(6H,m),2.00-2.07(2H,m),2.17-2.26(1H,m),2.67-2.87(2H,m),3.20(3H,s),3.61-3.81(4H,m),4.06-4.09(2H,m),4.22-4.25(2H,m),4.33-4.36(2H,m),6.98(1H,s),7.19(1H,t,J=7.8Hz),7.34(1H,s),7.86(1H,d,J=7.8 Hz),9.26(1H,d,J=7.8 Hz),10.6(1H,brs),11.6(1H,s),12.9(1H,s).

mass:504(M+1)⁺.

Working Example 63

Synthesis of the Compound of the Following Formula [63]:

According to a method similar to the procedures described in WorkingExamples 11-(17) and 1-(6), the hydrochloride (6 mg) of the objectivecompound [63] as a racemate was obtained as a deep purple solid from thebenzyl alcohol derivative (10 mg, 19 μmol) obtained in Working Example52-(2) and the racemic amine derivative [A-26].

Spectral data of the compound of the above formula [63] are shown below.

¹H-NMR(DMSO-d₆)δ:1.40-2.00(10H,m),2.00-2.12(2H,m),2.82-3.18(2H,m),3.40(3H,s),3.77-3.88(2H,m),4.02-4.10(2H,m),4.11-4.40(4H,m),4.66-4.73(1H,m),7.01-7.07(1H,m),7.18-7.24(2H,m),7.88 (1H,d,J=7.8Hz),9.28(1H,d,J=7.8 Hz),9.96 (1H,brs),11.6(1H,s),12.9(1H,s).

mass:504(M+1)⁺.

Working Example 64

Synthesis of the Compound of the Following Formula [64]:

According to a method similar to the procedures described in WorkingExamples 11-(17) and 1-(6), the hydrochloride (8 mg) of the objectivecompound [64] was obtained as a deep purple solid from the benzylalcohol derivative (10 mg, 19 μmol) obtained in Working Example 51-(2)and 4,4-difluoropiperidine.

Spectral data of the compound of the above formula [64] are shown below.

¹H-NMR(DMSO-d₆)δ:1.81-1.96(4H,m),2.03-2.10(2H,m),2.25-2.45(2H,m),2.45-2.56(2H,m),3.18-3.29(4H,m),4.05-4.11(2H,m),4.25-4.31(2H,m),4.44-4.73(2H,m),7.01(1H,s),7.21(1H,t,J=7.8Hz),7.32(1H,s),7.88(1H,d,J=7.8 Hz),9.27(1H,d,J=7.8 Hz),11.0(1H,brs),11.6(1H,s),12.9(1H,s).

mass:496(M+1)⁺.

Working Example 65

Synthesis of the Compound of the Following Formula [65]:

According to a method similar to the procedures described in WorkingExamples 11-(17) and 1-(6), the hydrochloride (5 mg) of the objectivecompound [65] was obtained as a brown solid from the benzyl alcoholderivative (10 mg, 19 μmol) obtained in Working Example 51-(2) and4-fluoropiperidine.

Spectral data of the compound of the above formula [65] are shown below.

¹H-NMR(DMSO-d₆)δ:1.80-2.00(4H,m),2.01-2.20(6H,m),3.02-3.35(4H,m),4.05-4.09(2H,m),4.25-4.29(2H,m),4.30-4.44(2H,m),4.92-5.08(1H,m),7.03(1H,s),7.21(1H,t,J=7.8Hz);7.32(1H,s),7.88(1H,d,J=7.8 Hz),9.27(1H,d,J=7.8 Hz),10.6(1H,brs),11.6(1H,s),12.9(1H,s).

mass:478(M+1)⁺.

Working Example 66

Synthesis of the Compound of the Following Formula [66]:

According to a method similar to the procedures described in WorkingExamples 11-(17) and 1-(6), the hydrochloride (5 mg) of the objectivecompound [66] was obtained as a brown solid from the benzyl alcoholderivative (10 mg, 19 μmol) obtained in Working Example 51-(2) anddiethylamine.

Spectral data of the compound of the above formula [66] are shown below.

¹H-NMR(DMSO-d₆)6:1.25(6H,t,J=7.5Hz),1.82-1.93(4H,m),2.00-2.10(2H,m),3.06-3.23(4H,m),4.05-4.11(2H,m),4.24-4.30(2H,m),4.37-4.40(2H,m),7.03(1H,s),7.22(1H,t,J=7.8Hz),7.24(1H,s),7.88 (1H,d,J=7.8 Hz),9.28(1H,d,J=7.8 Hz),9.94(1H,brs),11.6(1H,s),12.9(1H,s).

mass:448(M+1)⁺.

Working Example 67

Synthesis of the Compound of the Following Formula [67]:

According to a method similar to the procedure described in WorkingExample 43, the hydrochloride(8.1 mg) of the objective compound [67] asa racemate was obtained was obtained as a deep green solid from theracemic cyclic derivative (30 mg, 51 μmol) obtained in Working Example49-(2).

Spectral data of the compound of the above formula [67] are shown below.

¹H-NMR(DMSO-d₆)δ:1.14(3H,d,J=6.3 Hz),1.76-1.86(4H,m),2.08-2.28(2H,m),2.84(3H,d,J=4.8Hz)3.13-3.29(4H,m),3.40-3.60(2H,m),3.99-4.10(2H,m),4.10-4.17(1H,m),4.38-4.45(1H,m),4.60-4.66(1H,m),6.33(1H,s),6.88(1H,s)7.21(1H,t,J=7.8Hz),7.75(1H,d,J=7.8 Hz),8.98(1H,d,J=7.8 Hz),10.6(1H,brs),11.0(1H,s),12.5(1H,s).

mass:475(M+1)⁺.

Working Example 68

Synthesis of the Compound of the Following Formula [68]:

According to a method similar to the procedure described in WorkingExample 43, the hydrochloride (11 mg) of the objective compound [68] asa racemate was obtained as a deep green solid from the racemic cyclicderivative (20 mg, 34 μmol) obtained in Working Example 49-(2) andmorpholine.

Spectral data of the compound of the above formula [68] are shown below.

¹H-NMR(DMSO-d₆)δ:1.14(3H,d,J=6.0 Hz)1.71-1.86(4H,m),2.06-2.27(2H,m),3.17-3.31(4H,m),3.75-3.80(4H,m),4.01-4.17(1H,m),4.37-4.43(1H,m),4.58-4.64(1H,m),6.28(1H,s),6.80(1H,s),7.19(1H,t,J=7.8Hz),7.73(1H,d,J=7.8 Hz),8.96(1H,d,J=7.8 Hz),11.0 (1H,s),12.4(1H,s).

mass:462(M+1)⁺.

Working Example 69

Synthesis of the Compound of the Following Formula [69]:

According to a method similar to the procedure described in WorkingExample 43, the hydrochloride (11 mg) of the objective compound [69] asa racemate was obtained as a deep green solid from the racemic cyclicderivative (20 mg, 34 μmol) obtained in Working Example 49-(2) andpiperidine.

Spectral data of the compound of the above formula [69] are shown below.

¹H-NMR(DMSO-d₆)δ:1.14(3H,d,J=6.3Hz),1.73-1.87(6H,m),2.06-2.28(4H,m),2.72-2.85(2H,m),3.12-3.36(2H,m),4.01-4.18(3H,m),4.38-4.45(1H,m),4.53-4.65(1H,m),6.32(1H,s),6.88(1H,s),7.21(1H,t,J=7.8Hz),7.75(1H,d,J=7.8 Hz),8.98(1H,d,J=7.8 Hz),10.6 (1H,brs),11.0(1H,s),12.5(1H,s).

mass:460(M+1)⁺.

Working Example 70

Synthesis of the Compound of the Following Formula [70]:

According to a method similar to the procedure described in WorkingExample 1-(2), the above hydroxylamide (71 mg) was obtained as a paleyellow oil from the carboxylic acid derivative (82 mg, 190 μmol) whichis a starting material in Working Example 48-(1) and the abovehydroxylamine derivative [A-30] (98 mg, 282 μmol).

According to a method similar to the procedure described in WorkingExample 15-(4), the above 3-benzoisoxazolone derivative (40 mg) wasobtained as a yellow solid from the hydroxylamide derivative (71 mg, 80μmol) obtained in the above (1).

According to a method similar to the procedures described in WorkingExamples 1-(4) to 1-(6), the objective compound [70] (9 mg) was obtainedas a yellow solid from the 3-benzoisoxazolone derivative (40 mg)obtained in the above (2).

Spectral data of the compound of the above formula [70] are shown below.

¹H-NMR(DMSO-d₆)δ:1.82(4H,m),2.05(2H,m),4.05(2H,m),4.20(2H,m),6.91(2H,m),7.44(2H,m),7.87(1H,d,J=7.6Hz),9.05(1H,d=7.6 Hz),12.6(1H,s).

mass:364(M+1)⁺.

Working Example 71

Synthesis of the Compound of the Following Formula [71]:

According to a method similar to the procedure described in WorkingExample 48, the hydrochloride (84 mg) of the objective compound [71] wasobtained as a yellow solid from the carboxylic acid derivative (711 mg,1.27 mmol) which is a starting material in Working Example 48-(1) andthe hydrazine derivative [A-31] (576 mg, 1.65 mmol).

Spectral data of the compound of the above formula [71] are shown below.

¹H-NMR(DMSO-d₆)δ:3.00(3H,brs),3.55-3.75(2H,m),4.20-4.65(6H,m),6.93(1H,d,J=7.5 Hz),6.98(1H,d,J=7.5 Hz),7.26(1H,d,J=7.5Hz),7.53(1H,t,J=7.5 Hz),7.87(1H,d,J=7.5 Hz),9.24(1H,d,J=7.5Hz),9.78(1H,brs),11.5(1H,brs),12.8(1H,s).

mass:378(M+1)⁺.

Working Example 72

Synthesis of the Compound of the Following Formula [72]:

According to a method similar to the procedures described in WorkingExamples 48-(1) to 48-(3), the above racemic diol derivative (121 mg)was obtained as a yellow oil from the carboxylic acid (287 mg, 0.50mmol) which is a starting material in Working Example 48-(1) and theracemic hydrazine derivative [A-21].

The racemic diol derivative (370 mg, 0.705 mmol) obtained in the above(1) was dissolved in tetrahydrfuran (10 mL), and to this solution wereadded 1N sodium hydroxide (1 mL) and 35% aqueous formalin solution (2.5mL) at room temperature. The mixture was stirred at room temperatureovernight, and the resulting reaction solution was stirred at 50° C. for2 hours. This reaction solution was cooled down to room temperature,diluted with ethyl acetate, and washed successively with water andsaturated brine. The organic layer was dried over anhydrous magnesiumsulfate, filtered and concentrated in vacuo to obtain the racemic triolderivative (366 mg) as an orange oil.

The racemic triol derivative (55 mg, 0.10 mmol) obtained in the above(2) was dissolved in toluene (3 mL), and to the solution were addedacetic acid (0.3 mL) and pyrrolidine (0.3 mL). The solution was stirredunder heating at 50° C. for 2 days. The resulting reaction solution wascooled down to room temperature, poured into water, and extracted twicewith ethyl acetate. The organic layer was washed with saturated brine,dried over anhydrous magnesium sulfate, filtered and then concentratedin vacuo. The resulting residue was purified by a thin layerchromatography to obtain the racemic benzylamine derivative (46 mg) asan orange oil.

According to a method similar to the procedures described in WorkingExamples 1-(5) to 1-(6), the hydrochloride (5 mg) of the objectivecompound [72] as a racemate was obtained as a yellow solid from theracemic benzylamine derivative (10 mg, 17 μmol) obtained in the above(3).

Spectral data of the compound of the above formula [72] are shown below.

¹H-NMR(DMSO-d₆)δ:1.20(3H,d,J=6.5Hz),1.30-1.50(2H,m),1.80-2.10(7H,m),2.20-2.40(1H,m),3.02-3.25(2H,m),3.30-3.42(1H,m),3.42-3.55(1H,m),4.00-4.10(2H,m),4.30-4.50(3H,m),7.23(1H,d,J=8.0Hz),7.25(1H,t,J=8.0 Hz),7.87(1H,d,J=8.0 Hz),7.88(1H,d,J=8.0Hz),9.20(1H,d,J=8.0 Hz),10.50-10.60(1H,m),10.84(1H,s),12.94(1H,s).

mass:460(M+1)⁺.

Working Example 73

Synthesis of the Compound of the Following Formula [73]:

According to a method similar to the procedures described in WorkingExamples 72-(3), and 1-(5) to 1-(6), the hydrochloride (28 mg) of theobjective compound [73] as a racemate was obtained as a yellow solidfrom the racemic triol derivative (55 mg, 0.10 mmol) obtained in WorkingExample 72-(2) and piperidine.

Spectral data of the compound of the above formula [73] are shown below.

¹H-NMR(DMSO-d₆): 1.19(3H,d,J=6.5 Hz),1.30-1.50(2H,m),1.60-2.05(9H,m),2.20-2.38(1H,m),2.80-2.95(1H,m),2.95-3.10(1H,m),3.22-3.32(1H,m),3.36-3.46(1H,m),4.00-4.05(2H,m),4.30-4.50(3H,m),7.24(1H,d,J=8.0 Hz),7.26(1H,t,J=8.0 Hz),7.87(1H,d,J=8.0Hz),7.93(1H,d,J=8.0 Hz),9.20(1H,d,J=8.0Hz),10.15-10.25(1H,m),10.84(1H,s),12.95(1H,s).

mass:474(M+1)⁺.

Working Example 74

Synthesis of the Compound of the Following Formula [74]:

According to a method similar to the procedure of Example 11-(1), amixture (21.6 g) of the above 5-nitroquinoxalin-2-one derivative and theabove 8-nitroquinoxalin-2-one derivative was obtained as a yellow solidfrom ethyl (2-fluoro-3-iodophenyl)oxoacetate (21.5 g, 66.8 mmol)obtained according to a method similar to the method of the generalformula (II-d) described in WO 02/02550 and 3-nitrophenylenediamine(10.2 g, 66.6 mmol).

Chloromethyl 2-(trimethylsilyl)ethyl ether (10.0 mL, 56.3 mmol) wasadded to tetrahydrofuran solution (500 mL) containing a mixture (21.6 g)of the 5-nitroquinoxalin-2-one derivative and the8-nitroquinoxalin-2-one derivative obtained in the above (1), and thensodium hydride (2.30 g, 60% dispersion in oil, 57.3 mmol) was addedthereto under ice-cooling. After the resulting reaction solution wasstirred at room temperature for 1.5 hours, aqueous ammonium chloridesolution was added thereto, and the mixture was extracted withchloroform. After the organic layer was washed with saturated brine, itwas dried over anhydrous magnesium sulfate, filtered, and concentratedin vacuo. To the resulting residue was added 4N hydrogenchloride/1,4-dioxane solution (100 mL), and the solution was stirred atroom temperature for 1 hour. After removal of the insolubles byfiltration, the filtrate was concentrated in vacuo. The resultingresidue was purified by a column chromatography on silica gel to obtainthe above 5-nitroquinoxaline-2-one derivative (11.6 g) protected withSEM, as a yellow solid.

According to a method similar to the procedure described in WorkingExample 14-(5), the above ester derivative (8.06 g) was obtained as ayellow solid from the protected derivative with SEM (11.6 g, 21.4 mmol)obtained in the above (2).

The ester derivative (191 mg, 0.40 mmol) obtained in the above (3) wasdissolved in ethanol (10 mL), and to this solution were added saturatedaqueous ammonium chloride solution (2 mL) and iron powder (110 mg).After the resulting reaction solution was heated under reflux for 20minutes, saturated aqueous ammonium chloride solution (2 mL) and ironpowder (300 mg) were added thereto. Further, after this reactionsolution was heated under reflux for 20 minutes, iron powder (500 mg)was added thereto. Then, the resulting reaction solution was heatedunder reflux for 20 minutes, cooled down to room temperature, and waterand chloroform were added. After the reaction solution was filtered, thefiltrate was extracted with chloroform, and dried over anhydrousmagnesium sulfate. After removal of the insolubles by filtration, thefiltrate was concentrated in vacuo to obtain the aniline derivative (168mg) as a yellow solid.

Hydrazine monohydrate (5 mL) was added to ethanol solution (20 mL)containing the aniline derivative (1.60 g, 3.61 mmol) obtained in theabove (4), and the mixture was stirred at room temperature for 2 hours.The resulting reaction solution was concentrated in vacuo to obtain theabove hydrazide derivative (1.60 g) as a yellow solid.

According to a method similar to the procedure described in WorkingExample 11-(12), the above 3-indazolinone derivative (684 mg) wasobtained as a yellow solid from the hydrazide derivative (1.60 g, 3.61mmol) obtained in the above (5).

The 3-indazolinone derivative (10 mg, 24 μmol) obtained in the above (6)was dissolved in N,N-dimethylformamide (1 mL), and then1,5-diiodopentane (50 μL, 340 μmol) was added thereto. The mixture wasstirred at 100° C. for 3.5 hours. After the resulting reaction solutionwas cooled down to room temperature, it was concentrated in vacuo. Theresulting residue was purified by a thin layer chromatography to obtainthe cyclic derivative (2.5 mg) as a yellow solid.

According to a method similar to the procedure described in WorkingExample 1-(6), the objective compound [74] (1.8 mg) was obtained as ayellow solid from the cyclic derivative (2.5 mg, 5.1 μmol) obtained inthe above (7).

Spectral data of the compound of the above formula [74] are shown below.

¹H-NMR(DMSO-d₆)δ:1.62(2H,m),1.95(4H,m),3.20(4H,m),7.19(1H,t,J=7.8Hz),7.20-7.70(4H,m),7.86(1H,d,J=7.8Hz),9.18(1H,br),12.18(1H,br),12.78(1H,br).

mass:362(M+1)⁺.

Working Example 75

Synthesis of the Compound of the Following Formula [75]:

According to a method similar to the procedures described in WorkingExamples 1-(2) to 1-(6), the objective compound [75] (10 mg) wasobtained as a yellow solid from the carboxylic acid derivative (30 mg,45 μmol) obtained in Working Example 1-(1) and 6-amino-1-hexanol.

Spectral data of the compound of the above formula [75] are shown below.

¹H-NMR(DMSO)δ:1.60-2.00(8H,m),3.80-3.90(2H,m),4.15-4.30(2H,m),6.90-6.98(2H,m),7.43-7.65(2H,m),8.01(1H,d,J=7.6 Hz),9.51(1H,d,J=7.8Hz),12.8(1H,brs).

mass:394(M+1)⁺.

Working Example 76

Synthesis of the Compound of the Following Formula [76]:

Diisoproylethylamine (2.90 mL, 16.7 mmol), trioctylsilane (5.98 mL, 13.3mmol) and dichloro-bistriphenylphosphine palladium (777 mg, 1.11 mmol)were successively added to a mixed solution of N,N-dimethylformamide (75mL) and 1,4-dioxane (75 mL) containing the methoxyquinoxaline derivative(5.00 g, 11.1 mmol) obtained in Working Example 11-(3). The resultingreaction solution was stirred at 90° C. for 30 minutes, and then cooleddown to room temperature. After hexane and water were added to thisreaction solution, it was filtered through a Celite pad and the filtratewas extracted with ethyl acetate. The resulting organic layer was washedwith saturated brine, dried over anhydrous magnesium sulfate, filtered,and concentrated in vacuo. The resulting residue was purified by acolumn chromatography on silica gel to obtain the reduced derivative(4.10 g) as a gray solid.

According to a method similar to the procedures described in WorkingExamples 11-(9) to 11-(12), the above alcohol derivative (2.13 g) wasobtained as a yellow solid from the reduced derivative (4.10 g) obtainedin the above (1).

According to a method similar to the procedures described in WorkingExamples 11-(13) to 11-(16), and 11-(18), the hydrochloride (510 mg) ofthe objective compound [76] was obtained as a yellow solid from thereduced derivative (2.13 g) obtained in the above (2).

Spectral data of the compound of the above formula [76] are shown below.

¹H-NMR(DMSO)δ:1.75-2.40(3H,m),2.40-2.55(1H,m),3.00-3.35(2H,m),3.50-3.80(1H,m),3.82-4.35(3H,m),5.34-5.42(1H,m),6.96-7.27(3H,m),7.49-7.56(1H,m),7.84(1H,d,J=7.8Hz),9.20-9.30(1H,m),11.8-12.0(1H,m),12.7-12.8(1H,m).

mass:390(M+1)⁺.

Working Example 77

Synthesis of the Compound of the Following Formula [77]:

In the formula, the stereo chemistry of the position with the symbol *is of cis-configuration.

According to a method similar to the procedures described in WorkingExamples 1-(2) to 1-(3), the racemic benzoisothiazolone derivative (177mg) was obtained as a yellow oil from the carboxylic acid derivative(665 mg, 1.00 mmol) obtained in Working Example 1-(1) and the racematederivative [A-32].

According to a method similar to the procedures described in WorkingExamples 14-(12) to 14-(13), and 1-(6), the objective compound [77] (6mg) as a racemate was obtained as a yellow solid from the racemicbenzoisothiazolone derivative (177 mg, 264 mmol) obtained in the above(1).

Spectral data of the compound of the above formula [77] are shown below.

¹H-NMR(DMSO-d₆)δ:1.78-1.90(1H,m),1.95-2.04(2H,m),2.61-2.70(2H,m),2.85-2.92(2H,m),4.50-4.58(1H,m),4.70-4.82(2H,m),7.00-7.02(2H,m),7.50-7.65(2H,m),8.05(1H,d,J=7.3Hz),9.01(1H,d,J=6.6 Hz),12.8(1H,brs).

mass:392(M+1)⁺.

Example 78

Synthesis of the Compound of the Following Formula [78]:

According to a method similar to the procedures described in WorkingExamples 3-(1) to 3-(4) and 6, the hydrochloride (6 mg) of the objectivecompound [78] was obtained as a yellow solid from the carboxylic acidderivative (475 mg, 0.64 mmol) obtained in Working Example 14-(2) andthe sulfonamide derivative [A-3-5].

Spectral data of the compound of the above formula [78] are shown below.

¹H-NMR(DMSO-d₆)δ: 2.30-4.80(11H,m),7.10(1H,s),7.45-7.70(2H,m),7.97-8.05(1H,m),9.25-9.32(1H,m),12.9(1H,brs).

mass:473(M+1)⁺.

Working Example 79

Synthesis of the Compound of the Following Formula [79):

According to a method similar to the procedure described in WorkingExample 1-(4), the above phenol derivative (774 mg) was obtained as awhite solid from the methyl ester derivative (1.00 g, 1.74 mmol) whichis a starting material of Example 1-(1).

To tetrahydrofuran solution (20 mL) of the phenol derivative (774 mg,1.74 mmol) obtained in the above (1) was added 40% toluene solution(1.52 mL) containing triphenylphosphine (912 mg, 3.48 mmol), allylalcohol (202 mg, 3.48 mmol) and diethyl azodicarboxylate, and themixture was stirred at room temperature for 30 minutes. After additionof water (100 μL), the reaction solution was concentrated in vacuo, andthe resulting residue was purified by a column chromatography on silicagel to obtain the allyl ether derivative (725 mg) as a white solid.

Xylene solution (100 mL) containing the allyl ether derivative (725 mg,1.50 mmol) obtained in the above (2) was stirred at 180° C. for 3 days.The reaction solution was concentrated, and the resulting residue waspurified by a column chromatography on silica gel to obtain the aboveallyl rearrangement derivative (543 mg) as a white solid.

Chloromethyl 2-(trimethylsilyl)ethyl ether (400 μL, 2.26 mmol) was addedto tetrahydrofuran solution (20 mL) of the allyl rearrangementderivative (543 mg, 1.13 mmol) obtained in the above (3), underice-cooling, and sodium hydride (90 mg, 60% dispersion in oil, 2.26mmol) was added thereto. The mixture was stirred at room temperature for2 hours. After saturated aqueous ammonium chloride solution was added tothe reaction solution, it was extracted with ethyl acetate. The organiclayer was washed with water and saturated brine, dried over anhydrousmagnesium sulfate, and filtered. The filtrate was concentrated and theresulting residue was purified by a column chromatography on silica gelto obtain the protected derivative (695 mg) with SEM as a white solid.

Ozone was bubbled at −78° C. through a mixed solution of dichloromethane(14 mL) and methanol (6 mL) containing the derivative (1.00 g, 1.63mmol) protected with SEM obtained in the above (4), and the mixture wasstirred at the same temperature for 30 minutes. Nitrogen gas was bubbledthrough the solution, and dimethyl sulfide (5 ml) was added dropwisethereto. The reaction solution was warmed up to room temperature. Aftersodium tetrahydroborate (100 mg) was added thereto under ice-cooling,the mixture was stirred for 1 hour. After saturated aqueous ammoniumchloride solution was added to the reaction solution, it was extractedwith ethyl acetate. The organic layer was washed with water andsaturated brine, dried over anhydrous magnesium sulfate, and filtered.The filtrate was concentrated, and the resulting residue was purified bysilica gel chromatography on to obtain the hydroxyethyl derivative (800mg) as a pale yellow solid.

According to a method similar to the procedure described in WorkingExample 11-(8), the above derivative (820 mg) protected with THP wasobtained as a pale yellow solid from the hydroxyethyl derivative (800mg, 1.29 mmol) obtained in the above (5).

According to a method similar to the procedures described in WorkingExamples 1-(1) to 1-(3), the above benzoisothiazolone derivative (129mg) was obtained as a yellow solid from the derivative protected withTHP (820 mg, 1.16 mmol) obtained in the above (6). (8)

According to a method similar to the procedures described in WorkingExamples 11-(19), and 14-(12) to 14-(13), the above cyclic derivative(42 mg) was obtained as a yellow solid from the benzoisothiazolonederivative (110 mg, 118 μmol) obtained in the above (7).

According to a method similar to the procedure described in WorkingExample 11-(14), the above mesylated derivative (3.0 mg) was obtained asa yellow solid from the cyclic derivative (3.0 mg, 5.42 μmol) obtainedin the above (8).

The mesylated derivative (3.0 mg, 4.75 μmol) obtained in the above (9)was dissolved in toluene (450 μL), and to this solution were addedpyrrolidine (45 μL) and aqueous sodium hydrogencarbonate solution (45mg, 450 μL)) at room temperature. The mixture was stirred in a sealedtube at 130° C. for 12 hours. After this reaction solution was cooleddown to room temperature. it was extracted with ethyl acetate. Theorganic layer was washed with saturated brine, dried over anhydrousmagnesium sulfate, and filtered. The filtrate was concentrated, and theresulting residue was purified by a column chromatography on silica gelto obtain the pyrrolidinoethyl derivative (3.0 mg) as a pale yellowsolid.

According to a method similar to the procedure described in WorkingExample 1-(6), the above hydrochloride (2 mg) of the objective compound[79] was obtained as a yellow solid from the pyrrolidinoethyl derivative(2.5 mg, 4.12 μmol) obtained in the above (10).

Spectral data of the compound of the above formula [79] are shown below.

¹H-NMR(DMSO-d₆)δ:1.80-2.12(9H,m),2.18-2.33(3H,m),3.01-3.20(4H,m),3.53-3.70(2H,m),3.71-3.85(2H,m),4.30-4.41(2H,m),7.20(1H,d,J=8.7Hz),7.59(1H,d,J=8.7 Hz),7.66(1H,dd,J=7.6 Hz,8.0 Hz), 8.08(1H,d,J=7.6Hz),9.53(1H,d,J=8.0 Hz),10.15-10.32(1H,m),12.94(1H,s).

mass:477(M+1)⁺.

Working Example 80

Synthesis of the Compound of the Following Formula [80]:

According to a method similar to the procedures described in WorkingExamples 79-(10) and 1-(6), the hydrochloride (2.0 mg) of the objectivecompound [80] was obtained as a yellow solid from the mesylatedderivative (3 mg, 19 μmol) obtained in Working Example 79-(9) andpiperidine (45 μL).

Spectral data of the compound of the above formula [80] are shown below.

¹H-NMR(DMSO-d₆)δ:1.30-2.18(11H,m),2.19-2.36(3H,m),2.90-3.06(2H,m),3.10-3.21(2H,m),3.50-3.65(2H,m),3.72-3.88(2H,m),4.28-4.42(2H,m),7.21(1H,d,J=8.7Hz),7.57(1H,d,J=8.7 Hz),7.66(1H,d d,J=7.4 Hz,7.9 Hz),8.08(1H,d,J=7.4Hz),9.53(1H,d,J=7.9 Hz),9.70-9.90(1H,m),12.93(1H,s).

mass:491(M+1)⁺.

Working Example 81

Synthesis of the Compound of the Following Formula [81]:

According to a method similar to the procedure described in WorkingExamples 79-(10) and 1-(6), the hydrochloride (1.2 mg) of the objectivecompound [81] was obtained as a yellow solid from the mesylatedderivative (3 mg, 19 μmol) obtained in Working Example 79-(9) andN-methylpiperazine (45 μL).

Spectral data of the compound of the above formula [81] are shown below.

¹H-NMR(DMSO-d₆)6:1.90-4.00(23H,m),4.28-4.42(2H,m),7.20(1H,d,J=8.7Hz),7.55-7.75(2H,m),8.08(1H,d,J=7.5 Hz),9.30-9.48(1H,m),9.53(1H,d,J=8.0Hz),12.94(1H,s).

mass:506(M+1)⁺.

Working Example 82

Synthesis of the Compound of the Following Formula [82]:

According to a method similar to the procedures described in WorkingExamples 79-(10) and 1-(6), the hydrochloride (14.5 mg) of the objectivecompound [82] was obtained as a yellow solid from the mesylatedderivative (20 mg, 19 μmol) obtained in Working Example 79-(9) and4,4-difluoropiperidine (300 μL).

Spectral data of the compound of the above formula [82] are shown below.

¹H-NMR(DMSO-d₆)δ:1.92-2.18(4H,m),2.20-2.78(6H,m),3.12-3.38(5H,m),3.70-3.88(5H,m),4.28-4.42(2H,m),7.21(1H,d,J=8.5Hz),7.57(1H,d,J=8.9 Hz),7.66(1H,dd,J=7.4 Hz,8.2 Hz),8.08(1H,d,J=7.4Hz),9.53(1H,d,J=8.2 Hz),10.70-10.88(1H,m),12.93(1H,s).

mass:527(M+1)⁺.

Working Example 83

Synthesis of the Compound of the Following Formula [83]:

N,N-Diisopropylethylamine (12.8 mL, 73.5 mmol) was added to chloroformsolution (300 mL) containing the 3-indazolidinone derivative (10.0 g,19.6 mmol) obtained in Working Example 11-(12), and methanesulfonylchloride (5.00 mL, 64.6 mmol) was added dropwise thereto underice-cooling. The mixture was stirred for 30 minutes. Water was added tothe resulting reaction solution, and the organic layer was separated,washed successively with saturated aqueous sodium hydrogencarbonate,water and saturated brine, dried over anhydrous magnesium sulfate andfiltered. The filtrate was concentrated. The resulting residue wasdissolved in ethyl acetate, and the solution was washed with water. Theresulting organic layer was dried over anhydrous magnesium sulfate,filtered, and concentrated. The resulting residue was dissolved in1,4-dioxane (30 mL), and the pyrrolidine derivative [A-33] (11.9 g, 118mmol) was added thereto. The mixture was stirred at 85° C. for 2 hoursand then cooled down to room temperature. The reaction solution wasconcentrated and the resulting residue was purified by a columnchromatography on silica gel to produce the above amine derivative (9.61g) as a yellow solid.

According to a method similar to the procedures described in WorkingExamples 11-(14) to 11-(16), the above cyclic derivative (4.68 g) wasobtained as a yellow solid from the amine derivative (9.61 g, 16.2 mmol)obtained in the above (1).

According to a method similar to the procedure described in WorkingExample 40-(4), the above aldehyde derivative (1.62 g) was obtained asan orange solid from the cyclic derivative (2.34 g, 5.23 mmol) obtainedin the above (2).

To tetrahydrofuran solution (3 mL) containing the aldehyde derivative(171 mg, 384 μmol) obtained in the above (3) were added 2M isopropanolsolution (6.2 mL) containing ammonia and anhydrous magnesium sulfate(1.49 g). After the reaction solution was stirred for 1 hour, manganesedioxide (1.27 g) was added thereto, and the mixture was stirred for 15hours. The resulting reaction solution was filtered through a Celitepad, and the mother liquor was concentrated. The residue was purified bya silica gel chromatography to obtain the above nitrile derivative (106mg) as an orange solid.

To tetrahydrofuran solution (1 mL) containing the nitrile derivative (11mg, 24.8 μmol) obtained in the above (4) was added IM tetrahydrofuransolution (1 mL) containing lithium bis (trimethylsilyl)amide at roomtemperature, and the solution was stirred for 15 minutes. The reactionsolution was subjected to ice-cooling, and 6N hydrogen chloride/ethanol(1 mL) was added dropwise. The solution was stirred at room temperaturefor 30 minutes. After the reaction solution was diluted in diethylether, the resulting precipitates were filtered off, and washed withdiethyl ether. The resulting precipitates were dissolved in methanol,and the solution was diluted with ethyl acetate and water. AfterN,N-diisopropylethylamine (3 mL) and sodium chloride were added to themixed solution until the aqueous layer was saturated with them, theorganic layer was separated. The resulting organic layer was washed withsaturated brine, dried over anhydrous magnesium sulfate, and filtered.The filtrate was concentrated, and chloroform (2 mL) was added to theresulting residue. The mixture was stirred for 15 minutes to give asuspension. After 4N hydrogen chloride/1,4-dioxane (100 μL) was addeddropwise to the suspension, diethyl ether (3 mL) was added thereto. Theresulting precipitates were filtered off, washed with diethyl ether, anddried in vacuo to obtain the above amidine derivative (9.7 mg) as apurple solid.

The amidine derivative (4.6 mg, 8.63 μmol) obtained in the above (5) wassuspended in 1,1,3,3-tetramethoxypropane (500 μL). The suspension wasstirred in a sealed tube at 180° C. for 2 hours. The reaction solutionwas cooled down to room temperature, and diluted with methanol. Aftertriethylamine (1 mL) was added to the suspension, it was concentrated invacuo. The resulting residue was purified by a silica gel chromatographyto obtain the hydrochloride (0.90 mg) of the objective compound [83] asan orange solid.

Spectral data of the compound of the above formula [83] are shown below.

¹H-NMR(DMSO-d₆)δ:0.60-0.80(3H,m),1.00-4.00(8H,m),4.40-4.55(1H,m),5.32-5.42(1H,m),7.12-7.23(1H,m),7.48-7.57(1H,m),7.84-7.95(2H,m),8.09(1H,s),8.95-9.03(2H,m),9.42-9.53(1H,m),12.29-12.40(1H,m),12.81(1H,brs).

mass:482(M+1)⁺.

Working Example 84

Synthesis of the Compound of the Following Formula [84]:

The amidine derivative (5.0 mg, 9.4 μmol) obtained in Working Example83-(5) was suspended in acetonitrile (2 mL). To the suspension wereadded β-trifluoromethyl vinamidinium chloride (4.4 mg, 18.8 μmol)synthesized according to a method similar to the method described inTetrahedron Lett., 37(11) 1829 (1996) and 1.0 M methanol solution (22.5μL, 22.5 μmol) containing sodium methoxide. The mixture was stirred atroom temperature for 2.5 hours. Water was added to the reactionsolution, and it was extracted with a mixed solvent ofchloroform:methanol=9:1. The organic layer was washed with saturatedbrine, dried over anhydrous sodium sulfate, and filtered. The filtratewas concentrated, and the resulting residue was purified by a thin layerchromatography, followed by treatment according to a method similar tothe procedure described in Working Example 1-(6), thereby to obtain thehydrochloride (2.5 mg) of the objective compound [84] as a brown solid

Spectral data of the compound of the above formula [84] are shown below.

¹H-NMR(DMSO-d₆)δ:0.64-0.78(3H,m),1.35-1.45(1H,m),2.23-2.40(2H,m),2.52-2.63(1H,m),2.71-2.85(1H,m),2.94-3.08(1H,m),3.77-3.91(2H,m),4.44-4.51(1H,m),5.35-5.39(1H,m),7.13-7.20(1H,m),7.84-7.91(2H,m),8.12(1H,s),9.39(2H,s),9.45(1H,d,J=7.8Hz),12.28-12.30(1H,m),12.9(1H,s).

mass:550(M+1)⁺.

Working Example 85

Synthesis of the Compound of the Following Formula [85]:

3-(Dimethylamino)-2-methyl-2-propenal (4.5 mg, 39.4 μmol) and 1.0 Mmethanol solution (47.3 μL,47.3 μmol) containing sodium methoxide wereadded to methanol solution (3.0 mL) containing the amidine derivative(10.5 mg, 19.7 μmol) obtained in Working Example 83-(5). The solutionwas heated at reflux with stirring for 6.5 hours. Further,3-(dimethylamino)-2-methyl-2-propenal (27.0 mg, 238 μmol) and 1.0 Mmethanol solution (284 μL, 284 μmol) containing sodium methoxide wereadded thereto. The mixture was heated at reflux with stirring for 18hours. After the resulting reaction solution was cooled down to roomtemperature, water was added to the solution, which was then extractedwith a mixed solvent of chloroform:methanol=9:1. The organic layer waswashed with saturated brine, dried over anhydrous sodium sulfate,filtered. The filtrate was concentrated, and the resulting residue waspurified by a thin layer chromatography, followed by treatment accordingto a method similar to the procedure described in Working Example 1-(6),thereby to obtain the hydrochloride (4.8 mg) of the objective compound[85] as a deep purple solid.

Spectral data of the compound of the above formula (85] are shown below.

¹H-NMR(DMSO-d₆)δ:0.66-0.90(3H,m),1.38-1.47(1H,m),2.31(3H,s),2.25-2.41(2H,m),2.75-3.20(2H,m),3.82-3.93(2H,m),4.25-4.56(2H,m),5.36-5.42(1H,m),7.15-7.23(1H,m),7.87(1H,d,J=7.8Hz),7.89(1H,s),8.06(1H,s),8.81(2H,s),9.40-9.47(1H,m),12.2-12.4(1H,m),12.8(1H,s).

mass:496(M+1)⁺.

Working Example 86

Synthesis of the Compound of the Following Formula [86]:

The amidine derivative (9.9 mg, 18.6 μmol) obtained in Working Example83-(5) was suspended in ethanol (3 mL), and to the suspension were added2-methoxymethylene cyclohexanone (5.2 mg, 37.2 μmol) synthesizedaccording to a method similar to the method described in J. Heterocycl.Chem., 27, 1537 (1990) and sodium acetate (3.7 mg, 44.6 μmol). Themixture was stirred under heating at reflux for 6.5 hours. Then, afterfurther addition of 2-methoxymethylene cyclohexanone (10.4 mg, 74.3pmol) and sodium acetate (37.3 mg, 89.3 μmol), the mixture was stirredunder heating at reflux for 10 hours. The resulting reaction solutionwas cooled down to room temperature, and 10% aqueous sodium carbonatesolution (2 mL) was added thereto. The mixture was stirred at roomtemperature for 5 minutes and then extracted with a mixed solvent ofchloroform:methanol=9:1. The organic layer was washed with water andsaturated brine, dried over anhydrous sodium sulfate, and filtered. Thefiltrate was concentrated, and the resulting residue was purified bythin layer chromatography, followed by treatment according to a methodsimilar to the procedure described in Working Example 1-(6), thereby toobtain the hydrochloride (0.4 mg) of the objective compound [86] as abrown solid.

Spectral datum of the compound of the above formula [86] is shown below.

mass:536(M+1)⁺.

Working Example 87

Synthesis of the Compound of the Following Formula [87]:

To methanol solution (3.0 mL) containing the amidine derivative (10.0mg, 18.8 μmol) obtained in Working Example 83-(5) were addedacetylacetaldehyde dimetyhlacetal (5.0 μL, 37.6 μmol) and 1.0 M methanolsolution(45.1 μL, 45.1 μmol) containing sodium methoxide. The mixturewas stirred at 50° C. for 4.5 hours. Then, acetylacetaldehydedimetyhlacetal (10.0 μL, 75.2 μmol) and 1.0 M methanol solution (90.2μL, 90.2 μmol) containing sodium methoxide were added thereto. Themixture was stirred at 50° C. for 13 hours. After the resulting reactionsolution was cooled down to room temperature, water was added thereto,and the reaction solution was extracted with a mixed solvent ofchloroform:methanol=9:1. The organic layer was washed with saturatedbrine, dried over anhydrous sodium sulfate, and filtered. The filtratewas concentrated and the resulting residue was purified by a thin layerchromatography, followed by treatment according to a method similar tothe procedure described in Working Example 1-(6), thereby to obtain thehydrochloride (7.2 mg) of the objective compound [87] as a deep purplesolid.

Spectral data of the compound of the above formula [87] are shown below.

¹H-NMR(DMSO-d₆)δ:0.67-0.82(3H,m),1.40-1.45(1H,m),2.25-2.42(2H,m),2.58(3H,s),2.56-3.07(3H,m),3.83-3.98(2H,m),4.50-4.65(1H,m),5.34-5.41(1H,m),7.15-7.24(1H,m),7.40(1H,d,J=5.1Hz),7.88(1H,d,J=8.1 Hz),7.92(1H,s),8.10(1H,s),8.80(1H,d,J=5.1Hz),9.38-9.45(1H,m),12.2-12.3(1H,m),12.8(1H,s).

mass:496(M+1)⁺.

Working Example 88

Synthesis of the Compound of the Following Formula [88]:

Acetylacetone (7.7 μL, 75.1 μmol) and acetic acid (8.6 pL, 150 μmol)were added to 1-pentanol solution (4.0 mL) containing the amidinederivative (10.0 mg, 18.8 μmol) obtained in Working Example 83-(5). Themixture was stirred at 135° C. for 1.5 hours. Acetylacetone (77.2 μL,751 μmol) and acetic acid (86.0 μL, 1.50 mmol) were further addedthereto. The mixture was stirred at 135° C. for 27 hours. The resultingreaction solution was cooled down to room temperature, and saturatedaqueous sodium hydrogencarbonate was added to the reaction solution. Thesolution was extracted with a mixed solvent of chloroform:methanol=9:1.The organic layer was washed with water and saturated brine, dried overanhydrous sodium sulfate, and filtered. The filtrate was concentratedand the resulting residue was purified by a thin layer chromatography,followed by treatment according to a method similar to the proceduredescribed in Working Example 1-(6), thereby to obtain the hydrochloride(1.3 mg) of the objective compound [88] as a deep purple solid.

Spectral data of the compound of the above formula [88] are shown below.

¹H-NMR(DMSO-d₆)δ:0.65-0.79(3H,m),1.38-1.59(1H,m),2.08-2.50(3H,m),2.55(6H,s),2.78-3.08(2H,m),3.71-3.90(2H,m),4.44-4.49(1H,m),5.32-5.38(1H,m),7.13-7.26(1H,m),7.27(1H,s),7.90(1H,d,J=8.1Hz),7.90(1H,s),8.10(1H,s),9.40-9.47(1H,m),12.2-12.4(1H,m),12.7(1H,s).

mass:510(M+1)⁺.

Working Example 89

Synthesis of the Compound of the Following Formula [89]:

Hydroxylamine (12.6 mg, 181 μmol) andtriethylamine (25.2 μg, 181 μmol)were added to methanol solution (4.0 mL) containing the nitrilederivative (20 mg, 45.2 μmol) obtained in Working Example 83-(4). Themixture was stirred at room temperature for 10 hours. Hydroxylamine(12.6 mg, 181 μmol) and triethylamine (25.2 μg, 181 μmol) were furtheradded thereto. The mixture was stirred at room temperature for 3 days.The resulting reaction solution was concentrated in vacuo. Aceticanhydride (15 mL) was added to the resulting residue, and the mixturewas stirred at 100° C. for 24 hours. After the resulting reactionsolution was concentrated in vacuo, it was evaporated azeotropicallyusing toluene. The resulting residue was dissolved in tetrahydrofuran(10 mL) and methanol (10 mL), and 1N sodium hydroxide (10 mL) was addedto the solution. The solution was stirred at room temperature for 30minutes. After the resulting reaction solution was neutralized using 1Nhydrochloric acid, it was extracted with a mixed solvent ofchloroform:methanol=9:1. The organic layer was washed with water andsaturated brine, dried over anhydrous sodium sulfate, and filtered. Thefiltrate was concentrated and the resulting residue was purified by athin layer chromatography, followed by treatment according to a methodsimilar to the procedure described in Working Example 1-(6), thereby toobtain the hydrochloride (8.4 mg) of the objective compound [89] as anocher solid.

Spectral data of the compound of the above formula [89] are shown below.

¹H-NMR(DMSO-d₆)6:0.65-0.76(3H,m),1.35-1.41(1H,m),2.25-2.45(2H,m),2.69(3H,s),2.55-2.80(2H,m),2.91-3.05(1H,m),3.77-3.94(2H,m),4.42-4.51(1H,m),5.36-5.41(1H,m),7.14-7.21(1H,m),7.48(1H,s),7.62(1H,s),7.85(1H,d,J=7.8Hz),9.44(1H,d,J=7.8 Hz),12.25-12.29(1H,m),12.8(1H,s).

mass:486(M+1)⁺.

Working Example 90

Synthesis of the Compound of the Following Formula [90]:

According to a method similar to the procedures described in WorkingExamples 11-(10) to 11-(11), the above hydrazide derivative (24.3 g) wasobtained as an orange solid from the carboxylic acid derivative (24.4 g,36.9 mmol) obtained in Working Example 49-(1).

N,N-Diisopropylethylamine (13.3 mL, 76.3 mmol) was added to n-butanolsolution (200 mL) containing the hydrazide derivative (22.2 g, 27.3mmol) obtained in the above (1). The mixture was stirred at 120° C. for5 hours. After that, the resulting reaction solution was cooled down toroom temperature, and concentrated in vacuo to give a residue, to whichwas added ether (200 mL). The resulting solid was filtered off and driedin vacuo, followed by treatment according to a method similar to theprocedure described in Working Example 15-(4), thereby to obtain theabove alcohol derivative (17.5 g, 25.8 mmol) as a yellow solid

According to a method similar to the procedure described in WorkingExample 83-(1), the above amine derivative (10.6 g) was obtained as ayellow solid from the alcohol derivative (12.5 g, 18.4 mmol) obtained inthe above (2).

According to a method similar to the procedures described in WorkingExamples 1-(4) to 1-(5), the above cyclic derivative (7.06 g) wasobtained as a yellow solid from the amine derivative (9.78 g, 12.8 mmol)obtained in the above (3).

The cyclic derivative (15 mg, 24.5 μmol) obtained in the above (4) wasdissolved in a mixture of 1,2-dimethoxyethane and water (9:1) (1 mL). Tothe solution were added tetrakis(triphenylphospine)palladium (10 mg),potassium carbonate (10 mg) and dimethyl 2-pyridylboronate (10 mg), andthe mixture was stirred at 85° C. for 12 hours. Water and ethyl acetatewere added to the resulting reaction solution, and the organic layer wasseparated, then washed successively with water and saturated brine. Thisorganic layer was dried over anhydrous magnesium sulfate, filtered, andconcentrated. The resulting residue was purified by a silica gelchromatography to obtain the above pyridine derivative (5 mg) as ayellow solid.

According to a method similar to the procedure described in WorkingExample 11-(18), the trifluoroacetate (2.4 mg) of the objective compound[90] was obtained as a dark yellow solid from the pyridine derivative (5mg, 8.19 μmol) obtained in the above (5).

Spectral data of the compound of the above formula [90] are shown below.

¹H-NMR(DMSO-d₆)δ:0.68-0.70(3H,m),1.38-1.44(1H,m),2.24-2.38(1H,m),2.40-2.60(2H,m),2.70-2.79(1H,m),2.90-3.02(1H,m),3.76-3.86(2H,m),4.41-4.48(1H,m),5.38-5.40(1H,m),7.12-7.18(1H,m),7.40-7.42(1H,m),7.66(1H,s),7.70(1H,s),7.81-7.84(1H,m),7.90-8.00(1H,m),8.01-8.02(1H,m),8.70-8.72(1H,m),9.42-9.44(1H,m),12.3(1H,bs),12.7(1H,bs).

mass:481(M+1)⁺.

Working Example 91

Synthesis of the Compound of the Following Formula [91]:

According to a method similar to the procedures described in WorkingExamples 90-(5) and 11-(18), the trifluoroacetate (1.9 mg) of theobjective compound [91] was obtained as a dark yellow solid from thecyclic derivative (15 mg, 24.5 μmol) obtained in Working Example 90-(4)and pyrimidine-5-boronic acid.

Spectral datum of the compound of the above formula [91] is shown below.

mass:482(M+1)⁺.

Working Example 92

Synthesis of the Compound of the Following Formula [92]:

According to a method similar to the procedures described in WorkingExamples 90-(5) and 11-(18), the hydrochloride (7.7 mg) of the objectivecompound [92] was obtained as a dark yellow solid from the cyclicderivative (50 mg, 81.6 μmol) obtained in Working Example 90-(4) andthiazole-2-boronic acid.

Spectral datum of the compound of the above formula [92] is shown below.

mass:487(M+1)⁺.

Working Example 93

Synthesis of the Compound of the Following Formula [93]:

According to a method similar to the procedures described in WorkingExamples 90-(5) and 11-(18), the trifluoroacetate (2.6 mg) of theobjective compound [93] was obtained as a dark yellow solid from thecyclic derivative (10 mg, 16.3 μmol) obtained in Working Example 90-(4)and 5-acetyl-2-thiopheneboronic acid.

Spectral datum of the compound of the above formula [93] is shown below.

mass:528(M+1)⁺.

Working Example 94

Synthesis of the Compound of the Following Formula [94]:

According to a method similar to the procedures described in Example90-(5) and 11-(18), the trifluoroacetate (7.3 mg) of the objectivecompound [94] was obtained as a dark purple solid from the cyclicderivative (10 mg, 16.3 μmol) obtained in Working Example 90-(4) andpyridine-3-boronic acid.

Spectral datum of the compound of the above formula [94] is shown below.

mass:481(M+1)⁺.

Working Example 95

Synthesis of the Compound of the Following Formula [95]:

According to a method similar to the procedures described in Example90-(5) and 11-(18), the trifluoroacetate (5.9 mg) of the objectivecompound [95] was obtained as a dark yellow solid from the cyclicderivative (10 mg, 16.3 μmol) obtained in Working Example 90-(4) andpyridine-4-boronic acid.

Spectral datum of the compound of the above formula [95] is shown below.

mass:481(M+1)⁺.

Working Example 96

Synthesis of the Compound of the Following Formula [96]:

The cyclic derivative (20 mg, 32.7 μmol) obtained in Working Example90-(4) was dissolved in 1,4-dioxane (1 mL). To this solution were added2-pyrrolidinone (4.97 μL, 65.4 μmol),4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (5.68 mg, 9.81 μmol),tris(dibenzylideneacetone)dipalladium(0)-chloroform adduct (3.38 mg,3.27 μmol) and cesium carbonate (23.4 mg, 71.9 μmol). The mixture wasstirred at 110° C. for 1 hour under an argon atmosphere. The resultingreaction solution was cooled down to room temperature and concentratedin vacuo. The resulting residue was purified by a thin layerchromatography to obtain the above amide derivative (18 mg) as a yellowsolid.

According to a method similar to the procedure described in WorkingExample 1-(6), the hydrochloride (14 mg) of the objective compound [96]was obtained as a dark purple solid from the amide derivative (18 mg,29.2 μmol) obtained in the above (1).

Spectral data of the compound of the above formula [96] are shown below.

¹H-NMR(DMSO-d₆)δ:0.58-0.75(3H,m)1.22-1.45(1H,m),2.00-4.00(13H,m),4.35-4.53(1H,m),5.18-5.28(1H,m),7.07-7.20(1H,m),7.29-7.42(2H,m),7.78-7.86(1H,m),9.37-9.43(1H,m),12.25(1H,brs),12.56(1H,s).

mass:487(M+1)⁺.

Working Example 97

Synthesis of the Compound of the Following Formula [97]:

According to a method similar to the procedures described in WorkingExamples 96-(1) and 1-(6), the hydrochloride (3.3 mg) of the objectivecompound [97] was obtained as a dark purple solid from the cyclicderivative (10 mg, 16.3 μmol) obtained in Working Example 90-(4) andindole.

Spectral datum of the compound of the above formula [97] is shown below.

mass:519(M+1)⁺.

Working Example 98

Synthesis of the Compound of the Following Formula [98]:

According to a method similar to the procedures described in WorkingExamples 96-(1) and 1-(6), the trifluoroacetate (5.9 mg) of theobjective compound [98] was obtained as a dark purple solid from thecyclic derivative (10 mg, 16.3 μmol) obtained in Working Example 90-(4)and 3,5-dimethylpyrazole.

Spectral datum of the compound of the above formula [98] is shown below.

mass:498(M+1)⁺.

Working Example 99

Synthesis of the Compound of the Following Formula [99]:

According to a method similar to the procedures described in WorkingExamples 96-(1) and 1-(6), the trifluoroacetate (4.6 mg) of theobjective compound [99] was obtained as a dark purple solid from thecyclic derivative (10 mg, 16.3 mmol) obtained in Working Example 90-(4)and indazole.

Spectral datum of the compound of the above formula [99] is shown below.

mass:520(M+1)⁺.

Working Example 100

Synthesis of the Compound of the Following Formula [100]:

According to a method similar to the procedures described in WorkingExamples 96-(1) and 1-(6), the trifluoroacetate (6.3 mg) of theobjective compound [100] was obtained as a dark purple solid from thecyclic derivative (10 mg, 16.3 μmol) obtained in Working Example 90-(4)and 7-azaindole.

Spectral datum of the compound of the above formula [100] is shownbelow.

mass:520(M+1)⁺.

Working Example 101

Synthesis of the Compound of the Following Formula [101]:

According to a method similar to the procedures described in WorkingExamples 90-(5) and 11-(18), the hydrochloride (14.5 mg) of theobjective compound [101] was obtained as a dark purple solid from thecyclic derivative (30 mg, 49.0 μmol) obtained in Working Example 90-(4)and 3,5-dimethylphenylboronic acid.

Spectral datum of the compound of the above formula [101] is shownbelow.

mass:508(M+1)⁺.

Working Example 102

Synthesis of the Compound of the Following Formula [102]:

According to a method similar to the procedures described in WorkingExamples 90-(5) and 11-(18), the hydrochloride (7.0 mg) of the objectivecompound [102] was obtained as a dark purple solid from the cyclicderivative (10 mg, 16.3 μmol) obtained in Working Example 90-(4) andphenylboronic acid.

Spectral datum of the compound of the above formula [102] is shownbelow.

mass:480(M+1)⁺.

Working Example 103

Synthesis of the Compound of the Following formula [103]:

According to a method similar to the procedures described in WorkingExamples 90-(5) and 11-(18), the trifluoroacetate (5.1 mg) of theobjective compound [103] was obtained as a dark purple solid from thecyclic derivative (10 mg, 16.3 μmol) obtained in Working Example 90-(4)and 3-(trifluoromethoxy)phenylboronic acid.

Spectral datum of the compound of the above formula [103] is shownbelow.

mass:564(M+1)⁺.

Working Example 104

Synthesis of the Compound of the Following Formula [104]:

According to a method similar to the procedures described in WorkingExamples 90-(5) and 11-(18), the trifluoroacetate (9.0 mg) of theobjective compound [104] was obtained as a dark purple solid from thecyclic derivative (10 mg, 16.3 μmol) obtained in Working Example 90-(4)and 3,4-dimethoxyphenylboronic acid.

Spectral datum of the compound of the above formula [104] is shownbelow.

mass:540(M+1)⁺.

Working Example 105

Synthesis of the Compound of the Following Formula [105]:

According to a method similar to the procedures described in WorkingExamples 90-(5) and 11-(18), the hydrochloride (5.2 mg) of the objectivecompound [105] was obtained as a dark purple solid from the cyclicderivative (10 mg, 16.3 μmol) obtained in Working Example 90-(4) and2,2-difluorobenzodioxole-5-boronic acid.

Spectral datum of the compound of the above formula [105] is shownbelow.

mass:560(M+1)⁺.

Working Example 106

Synthesis of the Compound of the Following Formula [106]:

According to a method similar to the procedures described in WorkingExamples 90-(5) and 11-(18), the hydrochloride (1.1 mg) of the objectivecompound [106] was obtained as a dark purple solid from the cyclicderivative (10 mg, 16.3 μmol) obtained in Working Example 90-(4) and4-(difluoromethoxy)phenylboronic acid.

Spectral datum of the compound of the above formula [106] is shownbelow.

mass:546(M+1)⁺.

Working Example 107

Synthesis of the Compound of the Following Formula [107]:

According to a method similar to the procedures described in WorkingExamples 90-(5) and 11-(18), the trifluoroacetate (20.9 mg) of theobjective compound [107] was obtained as a dark purple solid from thecyclic derivative (20 mg, 32.6 μmol) obtained in Working Example 90-(4)and 3-methoxyphenylboronic acid.

Spectral datum of the compound of the above formula [107] is shownbelow.

mass:510(M+1)⁺.

Working Example 108

Synthesis of the Compound of the Following Formula [108]:

According to a method similar to the procedures described in WorkingExamples 90-(5) and 11-(18), the trifluoroacetate (14.3 mg) of theobjective compound [108] was obtained as a dark purple solid from thecyclic derivative (20 mg, 32.6 mmol) obtained in Working Example 90-(4)and 3-acetylphenylboronic acid.

Spectral datum of the compound of the above formula [108] is shownbelow.

mass:522(M+1)⁺.

Working Example 109

Synthesis of the Compound of the Following Formula [109]:

According to a method similar to the procedures described in WorkingExamples 90-(5) and 11-(18), the trifluoroacetate (13.2 mg) of theobjective compound [109] was obtained as a dark purple solid from thecyclic derivative (20 mg, 32.6 μmol) obtained in working Example 90-(4)and 3-acetamidophenylboronic acid.

Spectral datum of the compound of the above formula [109] is shownbelow.

mass:537(M+1)⁺.

Working Example 110

Synthesis of the Compound of the Following Formula [110]:

According to a method similar to the procedures described in WorkingExamples 90-(5) and 11-(18), the trifluoroacetate (8.8 mg) of theobjective compound [110] was obtained as a dark purple solid from thecyclic derivative (20 mg, 32.6 μmol) obtained in Working Example 90-(4)and 3-isopropylphenylboronic acid.

Spectral datum of the compound of the above formula [110] is shownbelow.

mass:522(M+1)⁺.

Working Example 111

Synthesis of the Compound of the Following Formula [111]:

According to a method similar to the procedures described in WorkingExamples 90-(5) and 11-(18), the trifluoroacetate (10.7 mg) of theobjective compound [111] was obtained as a dark purple solid from thecyclic derivative (20 mg, 32.6 μmol) obtained in Working Example 90-(4)and 3,5-difluorophenylboronic acid.

Spectral datum of the compound of the above formula [111] is shownbelow.

mass:516(M+1)⁺.

Working Example 112

Synthesis of the Compound of the Following Formula [112]:

According to a method similar to the procedures described in WorkingExamples 90-(5) and 11-(18), the trifluoroacetate (8.6 mg) of theobjective compound [112] was obtained as a dark purple solid from thecyclic derivative (10 mg, 16.3 μmol) obtained in Working Example 90-(4)and 2-methoxyphenylboronic acid.

Spectral datum of the compound of the above formula [112] is shownbelow.

mass:510(M+1)⁺.

Working Example 113

Synthesis of the Compound of the Following Formula [113]:

According to a method similar to the procedures described in WorkingExamples 90-(5) and 11-(18), the trifluoroacetate (5.3 mg) of theobjective compound [113] was obtained as a dark purple solid from thecyclic c derivative (10 mg, 16.3 μmol) obtained in Working Example90-(4) and 4-methoxyphenylboronic acid.

Spectral datum of the compound of the above formula [113] is shownbelow.

mass:510(M+1)⁺.

Working Example 114

Synthesis of the Compound of the Following Formula [114]:

According to a method similar to the procedures described in WorkingExamples 90-(5) and 11-(18), the trifluoroacetate (6.8 mg) of theobjective compound [114] was obtained as a dark purple solid from thecyclic derivative (10 mg, 16.3 μmol) obtained in Working Example 90-(4)and 2-nitrophenylboronic acid.

Spectral datum of the compound of the above formula [114] is shownbelow.

mass:525(M+1)⁺.

Working Example 115

Synthesis of the Compound of the Following Formula [115]:

According to a method similar to the procedures described in WorkingExamples 90-(5) and 11-(18), the trifluoroacetate (8.5 mg) of theobjective compound [115] was obtained as a dark purple solid from thecyclic derivative (10 mg, 16.3 μmol) obtained in Working Example 90-(4)and 4-aminophenylboronic acid.

Spectral datum of the compound of the above formula [115] is shownbelow.

mass:495(M+1)⁺.

Working Example 116

Synthesis of the Compound of the Following Formula [116]:

According to a method similar to the procedures described in WorkingExamples 90-(5) and 11-(18), the trifluoroacetate (1.3 mg) of theobjective compound [116] was obtained as a dark purple solid from thecyclic derivative (10 mg, 16.3 μmol) obtained in Working Example 90-(4)and 4-hydroxyphenylboronic acid.

Spectral datum of the compound of the above formula [116] is shownbelow.

mass:496(M+1)⁺.

Working Example 117

Synthesis of the Compound of the Following Formula [117]:

According to a method similar to the procedures described in WorkingExamples 90-(5) and 11-(18), the trifluoroacetate (10.8 mg) of theobjective compound [117] was obtained as a dark purple solid from thecyclic derivative (10 mg, 16.3 μmol) obtained in Working Example 90-(4)and 3-aminophenylboronic acid.

Spectral datum of the compound of the above formula [117] is shownbelow.

mass:495(M+1)⁺.

Working Example 118

Synthesis of the Compound of the Following Formula [118]:

According to a method similar to the procedures described in WorkingExamples 90-(5) and 11-(18), the trifluoroacetate (5.6 mg) of theobjective compound [118] was obtained as a dark purple solid from thecyclic derivative (10 mg, 16.3 μmol) obtained in Working Example 90-(4)and 4-(trifluoromethoxy)phenylboronic acid.

Spectral datum of the compound of the above formula [118] is shownbelow.

mass:564(M+1)⁺.

Working Example 119

Synthesis of the Compound of the Following Formula [119]:

According to a method similar to the procedures described in WorkingExamples 90-(5) and 11-(18), the trifluoroacetate (5.5 mg) of theobjective compound [119] was obtained as a dark purple solid from thecyclic derivative (10 mg, 16.3 μmol) obtained in Working Example 90-(4)and 4-(N,N-dimethylaminocarbonyl)phenylboronic acid.

Spectral datum of the compound of the above formula [119] is shownbelow.

mass:551(M+1)⁺.

Working Example 120

Synthesis of the Compound of the Following Formula [120]:

According to a method similar to the procedures described in WorkingExamples 90-(5) and 11-(18), the trifluoroacetate (4.8 mg) of theobjective compound [120] was obtained as a dark purple solid from thecyclic derivative (10 mg, 16.3 μmol) obtained in Working Example 90-(4)and 4-(pyrrolidine-1-carbonyl)phenylboronic acid.

Spectral datum of the compound of the above formula [120] is shownbelow.

mass:577(M+1)⁺.

Working Example 121

Synthesis of the Compound of the Following Formula [121]:

According to a method similar to the procedures described in WorkingExamples 90-(5) and 11-(18), the trifluoroacetate (7.3 mg) of theobjective compound [121] was obtained as a dark purple solid from thecyclic derivative (10 mg, 16.3 μmol) obtained in Working Example 90-(4)and 4-methylsulfonylphenylboronic acid.

Spectral datum of the compound of the above formula [121] is shownbelow.

mass:558(M+1)⁺.

Working Example 122

Synthesis of the Compound of the Following Formula [122]:

According to a method similar to the procedures described in WorkingExamples 43-(1) and 1-(6), the trifluoroacetate (1.5 mg) of theobjective compound [122] was obtained as a dark purple solid from thecyclic derivative (10 mg, 16.3 μmol) obtained in Working Example 90-(4)and pyrrolidine.

Spectral data of the compound of the above formula [122] are shownbelow.

¹H-NMR(DMSO-d₆)δ:0.60-0.80(3H,m),1.30-1.50(1H,m),1.95-4.38(15H,m),4.38-4.50(1H,m),5.18-5.28(1H,m),5.93(1H,s),6.30(1H,s),7.02-7.18(1H,m),7.65-7.75(1H,m),9.22-9.30(1H,m),12.02-12.23(2H,m).

mass:473(M+1)⁺.

Working Example 123

Synthesis of the Compound of the Following Formula [123]:

According to a method similar to the procedures described in WorkingExamples 43-(1) and 1-(6), the trifluoroacetate(1.7 mg) of the objectivecompound [123] was obtained as a dark purple solid from the cyclicderivative (10 mg, 16.3 μmol) obtained in Working Example 90-(4) and(S)-2-methoxymethylpyrrolidine.

Spectral datum of the compound of the above formula [123] is shownbelow.

mass:517(M+1)⁺.

Working Example 124

Synthesis of the Compound of the Following Formula [124]:

According to a method similar to the procedures described in WorkingExamples 43-(1) and 1-(6), the trifluoroacetate (1.5 mg) of theobjective compound [124] was obtained as a dark purple solid from thecyclic derivative (10 mg, 16.3 μmol) obtained in Working Example 90-(4)and 3-azabicyclo[3,2,2]nonane.

Spectral datum of the compound of the above formula [124] is shownbelow.

mass:527(M+1)⁺.

Working Example 125

Synthesis of the Compound of the Following Formula [125]:

According to a method similar to the procedures described in WorkingExamples 43-(1) and 1-(6), the trifluoroacetate (1.9 mg) of theobjective compound [125] was obtained as a dark purple solid from thecyclic derivative (10 mg, 16.3 μmol) obtained in Working Example 90-(4)and (R)-2-methoxymethylpyrrolidine.

Spectral datum of the compound of the above formula [125] is shownbelow.

mass:517(M+1)⁺.

Working Example 126

Synthesis of the Compound of the Following Formula [126]:

According to a method similar to the procedures described in WorkingExamples 43-(1) and 1-(6), the trifluoroacetate (1.4 mg) of theobjective compound [126] was obtained as a dark purple solid from thecyclic derivative (10 mg, 16.3 μmol) obtained in Working Example 90-(4)and 4-methylpiperidine.

Spectral datum of the compound of the above formula [126] is shownbelow.

mass:501(M+1)⁺.

Working Example 127

Synthesis of the Compound of the Following Formula [127]:

According to a method similar to the procedures described in WorkingExamples 43-(1) and 1-(6), the trifluoroacetate (1.7 mg) of theobjective compound [127] was obtained as a dark purple solid from thecyclic derivative (10 mg, 16.3 μmol) obtained in Working Example 90-(4)and hexamethyleneimine.

Spectral datum of the compound of the above formula [127] is shownbelow.

mass:501(M+1)⁺.

Working Example 128

Synthesis of the Compound of the Following Formula [128]:

According to a method similar to the procedures described in WorkingExamples 43-(1) and 1-(6), the trifluoroacetate (1.1 mg) of theobjective compound [128] was obtained as a dark purple solid from thecyclic derivative (10 mg, 16.3 μmol) obtained in Working Example 90-(4)and 1-(2-fluorophenyl)-piperazine.

Spectral datum of the compound of the above formula [128] is shownbelow.

mass:582(M+1)⁺.

Working Example 129

Synthesis of the Compound of the Following Formula [129]:

According to a method similar to the procedures described in WorkingExamples 43-(1) and 1-(6), the trifluoroacetate (1.1 mg) of theobjective compound [129] was obtained as a dark purple solid from thecyclic derivative (10 mg, 16.3 μmol) obtained in Working Example 90-(4)and 1-(2-pyridyl)piperazine.

Spectral datum of the compound of the above formula [129] is shownbelow.

mass:565(M+1)⁺.

Working Example 130

Synthesis of the Compound of the Following Formula [130]:

According to a method similar to the procedures described in WorkingExamples 43-(1) and 1-(6), the trifluoroacetate (1.0 mg) of theobjective compound [130] was obtained as a dark purple solid from thecyclic derivative (10 mg, 16.3 μmol) obtained in Working Example 90-(4)and 1-benzylpiperazine. Spectral datum of the compound of the aboveformula [130] is shown below.

mass:578(M+1)⁺.

Working Example 131

Synthesis of the Compound of the Following Formula [131]:

The amine derivative (320 mg, 421 μmol) obtained in Working Example90-(3) was dissolved in tetrahydrofuran (18 mL) and methanol (6 mL), and10% palladium-carbon catalyst (64 mg) was added thereto under a nitrogenatmosphere. The reaction system was substituted by hydrogen gas, and themixture was stirred at room temperature for 1 hour. The resultingreaction solution was filtered through a Celite pad to remove thecatalyst. The filtrate was concentrated in vacuo and the resultingresidue was purified by a silica gel chromatography to obtain thereduced derivative (290 mg) as a yellowish brown solid.

According to a method similar to the procedure described in WorkingExample 1-(4), the above phenol derivative (200 mg) was obtained as ayellowish brown solid from the reduced derivative (290 mg, 421 μmol)obtained in the above (1).

According to the procedure described in Working Example 72-(2), theabove hydroxymethyl derivative (210 mg) was obtained as a ocher solidfrom the phenol derivative (200 mg, 363 μmol) obtained in the above (2).

To a stirred chloroform suspension (10 mL) of the hydroxymethylderivative (210 mg, 363 μmol) obtained in the above (3) were addedtriethylamine (202 μL, 725 μmol), 4-dimethylaminopyridine (8.9 mg, 72.5μmol) and t-butyldiphenylsilyl chloride (141 μL, 544 μmol) at 0° C., andthe mixture was stirred at room temperature for 30 minutes. Afterfurther addition of triethylamine (606 μL, 2.17 mmol),4-dimethylaminopyridine (16.7 mg, 217 μmol) and t-butyldiphenylsilylchloride (324 μL, 1.63 mmol) with stirring at 0° C., the reactionsolution was stirred at room temperature for 1.5 hours. After additionof water, the resulting reaction solution was extracted with chloroform.The organic layer was washed with saturated brine, dried over anhydroussodium sulfate and filtered. The filtrate was concentrated, and theresulting residue was purified by a column chromatography on silica gelto obtain the protected derivative with TBDPS (257 mg) as a yellowishbrown solid.

According to a method similar to the procedures described in WorkingExamples 1-(5) and 15-(4), the above alcohol derivative (130 mg) wasobtained as a yellowish brown solid from the derivative protected withTBDPS (257 mg, 313 μmol) obtained in the above (4).

According to a method similar to the procedures described in WorkingExamples 11-(17) and 1-(6), the hydrochloride (4.6 mg) of the objectivecompound [131] was obtained as a yellow green solid from the alcoholderivative (11.3 mg, 20.1 μmol) obtained in the above (5) andpiperidine.

Spectral data of the compound of the above formula [131] are shownbelow.

¹H-NMR(DMSO-d₆)δ:0.60-0.68(3H,m),1.24-1.43(1H,m),1.63-1.85(6H,m),2.00-2.26(1H,m),2.71-3.46(8H,m),3.54-3.77(1H,m),3.78-3.97(1H,m),4.30-4.52(3H,m),5.33-5.43(1H,m),7.18-7.24(1H,m),7.21(1H,d,J=8.4 Hz),7.75-7.90(1H,m),7.88(1H,d,J=7.5Hz),9.43-9.59(1H,m),9.98-10.0 (1H,m),12.7-12.9(1H,m),12.9(1H,s).

mass:501(M+1)⁺.

Working Example 132

Synthesis of the Compound of the Following Formula [132]:

According to a method similar to the procedures described in WorkingExamples 11-(17) and 1-(6), the hydrochloride (6.9 mg) of the objectivecompound [132] was obtained as a dark green solid from the alcoholderivative (18.4 mg, 32.7 μmol) obtained in Working Example 131-(5) andN-methylpiperazine.

Spectral datum of the compound of the above formula [132] is shownbelow.

mass:516(M+1)⁺.

Working Example 133

Synthesis of the Compound of the Following Formula [133]:

According to a method similar to the procedures described in WorkingExamples 11-(17) and 1-(6), the hydrochloride (11.7 mg) of the objectivecompound [133] was obtained as a dark green solid from the alcoholderivative (20.7 mg, 36.8 μmol) obtained in Working Example 131-(5) andN-acetylpiperazine.

Spectral datum of the compound of the above formula [133] is shownbelow.

mass:544(M+1)⁺.

Working Example 134

Synthesis of the Compound of the Following Formula [134]:

According to a method similar to the procedures described in WorkingExamples 83-(1), 11-(14) to 11-(16) and 11-(18), the hydrochloride (9.6mg) of the objective compound [134] was obtained as a dark green solidfrom the alcohol derivative (140 mg, 351 μmol) obtained in WorkingExample 76-(2).

Spectral data of the compound of the above formula [134] are shownbelow.

¹H-NMR(DMSO-d₆)δ:0.68(3H,m),1.34(1H,m),2.00-3.10(5H,m),3.40-4.00(2H,m),4.46(1H,m),5.24(1H,brs),6.94(2H,m),7.14(1H,m), 7.48(1H,m),7.83(1H,d,J=8.4 Hz), 9.43(1H, m),12.2(1H,brs),12.6(1H,brs).

mass:404(M+1)⁺.

Working Example 135

Synthesis of the Compound of the Following Formula [135]:

According to a method similar to the procedure described in WorkingExample 11-(14), the above mesylated derivative (270 mg) was obtained asa yellow solid from the cyclic derivative (240 mg, 536 μmol) obtained inWorking Example 83-(2).

According to a method similar to the procedure described in WorkingExample 131-(1), the above methyl derivative (24 mg) was obtained as ayellow solid from the mesylated derivative (90 mg, 171 μmol) obtained inthe above (1).

According to a method similar to the procedure described in WorkingExample 1-(6), the hydrochloride (15 mg) of the objective compound [135]was obtained as a dark purple solid from the methyl derivative (24 mg,55.6 μmol) obtained in the above (2).

Spectral data of the compound of the above formula [135] are shownbelow.

¹H-NMR(DMSO-d₆)δ:0.60-0.75(3H,m),1.25-1.41(1H,m),2.20-2.61(6H,m),2.63-2.82(1H,m),2.85-3.10(1H,m),3.55-3.90(2H,m),4.38-4.50(1H,m),5.18-5.25(1H,m),6.72-6.79(1H,m),6.82-6.90(1H,m),7.02-7.22(1H,m),7.80-7.86(1H,m),9.35-9.45(1H,m),12.20-12.31(1H,m),12.55-12.65(1H,m).

mass:418(M+1)⁺.

Working Example 136

Synthesis of the Compound of the Following Formula [136]:

According to a method similar to the procedure described in WorkingExamples 11-(17) and 1-(6), the hydrochloride (49 mg) of the objectivecompound [136] was obtained as a yellow solid from the mesylatedderivative (80 mg, 179 μmol) obtained in Working Example 135-(1) andmorpholine.

Spectral data of the compound of the above formula [136] are shownbelow.

¹H-NMR(DMSO-d₆)δ:0.62-0.78(3H,m),1.30-1.42(1H,m),2.22-3.40(9H,m),3.60-4.00(6H,m),4.35-4.52(3H,m),5.12-5.23(1H,m),7.05(1H,d,J=0.9Hz),7.17(1H,dd,J=7.9 Hz,8.3 Hz),7.37(1H,d,J=0.9 Hz), 7.88(1H,d,J=7.9Hz),9.44(1H,d,J=8.3 Hz),10.82-11.01(1H,m),12.24 (1H,s),12.89(1H,s).

mass:503(M+1)⁺.

Working Example 137

Synthesis of the Compound of the Following Formula [137]:

To tetrahydrofuran solution (5 mL) containing the mesylated derivative(80 mg, 179 μmol) obtained in Example 135-(1) was added 1M methanolsolution containing sodium methoxide at room temperature. The mixturewas stirred at 60° C. for 3 hours. The reaction solution was cooled downto room temperature, diluted with chloroform, and washed successivelywith water and saturated brine. The organic layer was dried overanhydrous magnesium sulfate and filtered. The filtrate was concentratedin vacuo and the resulting residue was purified by a silica gelchromatography to produce the methoxymethyl derivative (56 mg) as ayellow solid.

According to a method similar to the procedure described in WorkingExample 11-(18), the hydrochloride (40 mg) of the objective compound[137] was obtained as a purple solid from the methoxymethyl derivative(56 mg, 121 μmol) obtained in the above (1).

Spectral data of the compound of the above formula [137] are shownbelow.

¹H-NMR(DMSO-d₆)δ:0.60-0.80(3H,m),1.20-1.50(1H,m),2.20-3.10(5H,m),3.56(3H,s),3.72-4.60(5H,m),5.20-5.31(1H,m),6.89-7.00(2H,m),7.10-7.22(1H,m),7.80-7.88(1H,m),9.38-9.48(1H,m),12.20-12.38(1H,m),12.62-12.70(1H,m).

mass:448(M+1)⁺.

Working Example 138

Synthesis of the Compound of the Following Formula [138]:

To tetrahydrofuran solution (5 mL) containing the mesylated derivative(50 mg, 95 μmol) obtained in Example 135-(1) was added 1Mtetrahydrofuran solution (5 mL) containing sodium 2-methoxyethoxide atroom temperature, and the mixture was stirred at 60° C. for 3 hours. Thereaction solution was cooled down to room temperature, diluted withchloroform, and washed successively with water and saturated brine. Theorganic layer was dried over anhydrous magnesium sulfate, and filtered.The filtrate was concentrated in vacuo, and the resulting residue waspurified by a silica gel chromatography to obtain themethoxyethoxymethyl derivative (12 mg) as a yellow solid.

According to a method similar to the procedure described in WorkingExample 11-(18), the hydrochloride (6.2 mg) of the objective compound[138] was obtained as a dark purple solid from the methoxyethoxymethylderivative (12 mg, 23.7 μmol) obtained in the above (1).

Spectral data of the compound of the above formula [138] are shownbelow.

¹H-NMR(DMSO-d₆)δ:0.60-0.78(3H,m),1.20-1.50(1H,m),2.20-4.20(14H,m),4.38-4.52(1H,m),4.59(2H,s),5.19-5.27(1H,m),6.90-6.98(2H,m),7.08-7.12(1H,m),7.81-7.87(1H,m),9.35-9.45(1H,m),12.18-12.32(1H,m),12.55-12.70(1H,m).

mass:492(M+1)⁺.

Working Example 139

Synthesis of the Compound of the Following Formula [139]:

To tetrahydrofuran solution (100 mL) containing the aldehyde derivative(197 mg, 442 pool) obtained in Working Example 83-(3) was dropwise added1M diethyl ether solution (2.64 mL) containing allyl magnesium bromideat −78° C., and the mixture was stirred at the same temperature for 15minutes. After acetic acid (500 μL) was added dropwise to the reactionsolution, it was warmed up to room temperature. This reaction solutionwas concentrated in vacuo, and the resulting residue was purified by asilica gel chromatography to obtain the diol derivative (127 mg), whichwas a diastereomer mixture, as a yellow solid.

The alcohol derivative (74 mg) which was a diastereomer mixture obtainedin the above (1) was resolved by Chiralpack AD to produce the chiralalcohol derivative A (430 mg) with a shorter retention time as a yellowsolid and the chiral alcohol derivative B (38 mg) with a longerretention time as a yellow solid.

To N,N-dimethylformamide solution (15 mL) containing the chiral alcoholderivative A (30 mg, 61.5 μmol) obtained in the above (2) was addedsodium hydride (16 mg, 60% dispersion in oil) at 70° C., and the mixturewas stirred at the same temperature for 10 minutes. The resultingreaction solution was kept at 0° C., and allyl bromide (34 μL) was addedthereto, and then the mixture was further stirred for 30 minutes. Afteracetic acid (100 μL) was added dropwise, pyrrolidine (55 μL) was addeddropwise thereto. This reaction solution was diluted with ethyl acetate,and the organic layer was washed with saturated brine, dried overanhydrous magnesium sulfate and filtered. The filtrate was concentratedin vacuo, and the resulting residue was purified by a columnchromatography on silica gel to obtain the allyl ether derivative (5.1mg) as a yellow solid.

To dichloromethane solution (3 mL) containing the allyl ether derivative(5.1 mg, 9.77 μmol) obtained in the above (3) was addedbenzylidene-bis(tricyclohexylphosphine)dichlorolutenium (795 μg) at roomtemperature under an argon atmosphere, and the mixture was stirred for15 hours. The resulting reaction solution was purified by a columnchromatography on silica gel to obtain the cyclic derivative (5.0 mg) asa yellow solid.

According to a method similar to the procedure described in WorkingExample 131-(1), the above tetrahydropyran derivative (5.0 mg) wasobtained as a yellow solid from the cyclic derivative (5.0 mg, 10.0μmol) obtained in the above (4).

According to a method similar to the procedure described in WorkingExample 1-(6), the hydrochloride (2.0 mg) of the objective compound[139] was obtained as a dark purple solid from the tetrahydropyranderivative (2.0 mg, 3.98 μmol) obtained in the above (5).

Spectral data of the compound of the above formula [139] are shownbelow.

¹H-NMR(DMSO-d₆)δ:0.52-0.78(3H,m),1.22-1.98(8H,m),2.88-3.08(1H,m),3.50-4.11(6H,m),4.35-4.53(3H,m),5.18-5.35(1H,m),6.90-7.00(2H,m),7.10-7.22(1H,m),7.81-7.88(1H,m),9.38-9.48(1H,m),12.20-12.35(1H,m),12.61(1H,brs).

mass:488(M+1)⁺.

Working Example 140

Synthesis of the Compound of the Following Formula [140]:

According to a method similar to the procedures described in WorkingExamples 139-(3) to 139-(4), 131-(1) and 1-(6), the hydrochloride (3.2mg) of the objective compound [140] was obtained as a dark purple solidfrom the chiral alcohol derivative (38 mg, 77.9 μmol) obtained inWorking Example 139-(2).

Spectral datum of the compound of the above formula [140] is shownbelow.

mass:488(M+1)⁺.

Working Example 141

Synthesis of the Compound of the Following Formula [141]:

According to a method similar to the procedures described in workingExamples 11-(14), 131-(1) and 1-(6), the hydrochloride (1.8 mg) of theobjective compound [141] was obtained as a dark purple solid from thecyclic derivative (8.5 mg) obtained in Working Example 11-(16).

Spectral data of the compound of the above formula [141] are shownbelow.

¹H-NMR(DMSO-d₆)δ:2.00-2.70(7H,m),2.80-4.40(6H,m),5.32(1H,m),6.80-7.40(3H,m),7.80(1H,m),9.18(1H,m),11.8(1H,m),12.6(1H,m

mass:404(M+1)⁺.

Working Example 142

Synthesis of the Compound of the Following Formula [142]:

According to a method similar to the procedures described in WorkingExamples 11-(10) to 11-(11), 90-(2) and 15-(4), the indazolinonederivative (250 mg) was obtained as a yellowish brown viscous liquidfrom the carboxylic acid (382 mg, 696 μmol) which is a starting materialof Example 48-(1), and the hydrazine derivative [A-34] (304 mg, 1.05mmol).

According to a method similar to the procedure described in Working.Example 83-(1), the above amine derivative (6.8 mg) was obtained as ayellowish brown viscous liquid from the indazolinone derivative (38.0mg, 62.0 μmol) obtained in the above (1).

According to a method similar to the procedures described in WorkingExamples 1-(4) to 1-(6), the hydrochloride (1.4 mg) of the objectivecompound [142] was obtained as a dark purple solid from the aminederivative (6.8 mg, 9.77 μmol) obtained in the above (2).

Spectral data of the compound of the above formula [142] are shownbelow.

¹H-NMR(DMSO-d₆)δ: 0.60-0.72(3H,m),1.25-1.49(1H,m),1.51(3H,d, J=6.9Hz),2.20-2.30(1H,m),2.68-3.23(4H,m),3.66-3.82(1H,m),4.79-4.91(1H,m),5.21-5.25(1H,m),7.00(1H,d,J=8.1Hz),7.09-7.19(2H,m),7.51(1H,d,J=8.1 Hz),7.85(1H,d,J=7.2Hz),9.33-9.42(1H,m),12.15-12.24(1H,m),12.7(1H,s).

mass:418(M+1)⁺.

Working Example 143

Synthesis of the Compound of the Following Formula [143]:

According to a method similar to the procedures described in WorkingExamples 11-(17) and 1-(6), the hydrochloride (6.4 mg) of the objectivecompound [143] was obtained as a yellowish green solid from the alcoholderivative (10.0 mg, 17.7 μmol) obtained in Working Example 131-(5) andcyclopentylamine.

Spectral data of the compound of the above formula [143] are shownbelow.

¹H-NMR(DMSO-d₆)δ:0.52-0.74(3H,m),1.06-1.29(1H,m),1.46-1.59(2H,m),1.59-1.80(4H,m),1.97-2.07(2H,m),2.09-2.27(1H,m),2.82-3.16(2H,m),3.46-3.59(2H,m),3.60-3.95(3H,m),4.09-4.39(2H,m),4.39-4.46(1H,m),5.21-5.42(1H,m),7.15-7.22(1H,m),7.19(1H,d,J=8.4Hz),7.77-7.84(1H,m),7.87(1H,d,J=7.5 Hz),9.05-9.15(1H,m),9.23-9.34(1H,m),9.42-9.55(1H,m),12.66-12.70(1H,m),12.8(1H,s

mass:501(M+1)⁺.

Example 144

Synthesis of the Compound of the Following Formula [144]:

According to a method similar to the procedures described in WorkingExamples 11-(17) and 1-(6), the hydrochloride (4.7 mg) of the objectivecompound [144] was obtained as a yellowish green solid from the alcoholderivative (10.0 mg, 17.7 μmol) obtained in Working Example 131-(5) andcyclopropylamine.

Spectral data of the compound of the above formula [144] are shownbelow.

¹H-NMR(DMSO-d₆)δ:0.60-0.90(5H,m),0.90-0.96(2H,m)1.10-1.30(1H,m),2.05-2.25(1H,m),2.61-2.80(2H,m),2.93-3.15(2H,m),3.55-3.80(1H,m),3.82-4.02(2H,m),4.27-4.51(3H,m),5.24-5.42(1H,m),7.14-7.23(1H,m),7.17(1H,d,J=8.7 Hz),7.73-7.80(1H,m),7.87(1H, d,J=7.8Hz),9.35-9.60(3H,m),12.7-12.8(1H,m),12.9(1H,s).

mass:473(M+1)⁺.

Working Example 145

Synthesis of the Compound of the Following Formula [145]:

According to a method similar to the procedures described in WorkingExamples 11-(17) and 1-(6), the hydrochloride (4.7 mg) of the objectivecompound [145] was obtained as a yellowish green solid from the alcoholderivative (10.0 mg, 17.7 μmol) obtained in Working Example 131-(5) andt-butylamine.

Spectral data of the compound of the above formula [145] are shownbelow.

¹H-NMR(DMSO-d₆)δ:0.55-0.77(3H,m),1.05-1.39(1H,m),1.40(9H,s),2.03-2.31(1H,m),2.80-3.05(2H,m),3.35-3.79(2H,m),3.80-4.03(2H,m),4.09-4.38(2H,m),4.39-4.51(1H,m),5.27-5.38(1H,m),7.14-7.23(1H,m),7.19(1H,d,J=8.7Hz),7.81-7.89(1H,m),7.86(1H,d,J=7.8Hz),8.60-8.85(1H,m),9.05-9.25(1H,m),9.35-9.65(1H,m),12.7-12.9(1H,m),12.9(1H,s).

mass:489(M+1)⁺.

Working Example 146

Synthesis of the Compound of the Following Formula [146]:

According to a method similar to the procedures described in WorkingExamples 11-(17) and 1-(6), the hydrochloride (5.0 mg) of the objectivecompound [1461 was obtained as a yellowish green solid from the alcoholderivative (10.0 mg, 17.7 μmol) obtained in Working Example 131-(5) andtrifluoroethylamine.

Spectral data of the compound of the above formula [146] are shownbelow.

¹H-NMR(DMSO-d₆)δ:0.59-0.92(3H,m),1.05-1.54(1H,m),1.90-2.15(1H,m),2.85-3.20(2H,m),3.45-4.10(6H,m),4.10-4.39(2H,m),4.40-4.46(1H,m),5.21-5.42(1H,m),7.13-7.23(1H,m),7.16(1H,d,J=8.7Hz),7.70-7.85(1H,m),7.87(1H,d,J=7.5Hz),9.40-9.65(1H,m),12.6-12.8(1H,m),12.8(1H,s).

mass:515(M+1)⁺.

Reference Example 1

Synthesis of the Compound of the Following Formula [A-1]:

2-Amino-3-nitrophenol (77 mg, 0.50 mmol) was dissolved inN,N-dimethylformamide (2 mL), and to this solution were addedsuccessively imidazole (68 mg, 1.00 mmol) and t-butyldimethylsilylchloride (90 mg, 0.60 mmol) under ice-cooling. The mixture was stirredat room temperature overnight. The resulting reaction solution wasdiluted with ethyl acetate, and washed successively with water andsaturated brine. The organic layer was dried over anhydrous magnesiumsulfate, filtered, and concentrated in vacuo to obtain the aboveprotected derivative with TBS (140 mg) as a deep orange oil.

The protected derivative with TBS (140 mg, 0.50 mmol) obtained in theabove (1) was dissolved in ethyl acetate (2 mL), and to the solution wasadded gradually N-bromosuccinimide (98 mg, 0.55 mmol) in a water-bath.The reaction solution was stirred at room temperature for 10 minutes.The resulting reaction solution was diluted with ethyl acetate, andwashed successively with saturated aqueous sodium sulfite, aqueoussodium hydrogencarbonate and saturated brine. The organic layer wasdried over anhydrous magnesium sulfate, filtered, and concentrated invacuo to obtain the above brominated derivative (169 mg) as a deepyellow solid.

The brominated derivative (165 mg, 0.48 mmol) obtained in the above (2)was dissolved in tetrahydrofuran (2 mL), and 5% platinum carbon catalyst(33 mg) was added thereto under a nitrogen atmosphere. Aftersubstitution of the atmosphere of the reaction system with hydrogen, thesolution was stirred at room temperature for 8 hours. The resultingreaction solution was filtered through a Celite pad to remove thecatalyst, and the filtrate was concentrated in vacuo to obtain theobjective compound [A-1] (151 mg) as a deep brown oil.

Reference Example 2 Synthesis of the Compound of the Following Formula[A-2]:

Ethyl (2-fluoro-3-iodophenyl)oxoacetate (10.0 g, 31.1 mmol) according toa method similar to the method of general formula (II-d) described in WO02/02550 pamphlet was dissolved in N,N-dimethylformamide (100 mL) andmethanol (100 mL), and to this solution was added sodiumhydrogencarbonate (7.84 g, 93.3 mmol). The atmosphere in the reactionsystem was substituted with nitrogen gas. Palladium acetate(II) (75 mg,3.11 mmol) and 1,1′-bis(diphenylphosphino)ferrocene (185 mg, 3.11 mmol)were added thereto at room temperature under a nitrogen atmosphere, andthen the atmosphere in the reaction system was substituted by carbonmonooxide gas. This solution was stirred at 70° C. for 2 hours, cooleddown to room temperature, diluted with chloroform, and washedsuccessively with water and saturated aqueous ammonium chloride. Theorganic layer was dried over anhydrous magnesium sulfate, filtered, andconcentrated. The resulting residue was purified by a columnchromatography on silica gel to obtain the objective compound [A-2](2.90 g) as a yellow solid.

Reference Example 3

Synthesis of the Compounds of the Following Formulae [A-3-1] to [A-3-5]:

According to a method similar to the method described in Journal ofSynthetic Organic Chemistry, Japan, 59(8) 779 (2001) and the procedureof Reference Example 1-(1), (R)-1-amino-2-propanol,(S)-1-amino-2-propanol, (R)-2-amino-1-propanol, (S)-2-amino-1-propanol,and 2-aminoethanol were respectively sulfonated and silylated to obtainthe corresponding O-silyl-sulfonamide derivatives [A-3-1] to [A-3-5].

Reference Example 4

Synthesis of the Compound of the Following Formula [A-4]:

According to a method similar to the method described in Bull. Chem.Soc. Jpn., 57(7) 2019 (1984), the above TBS derivative was obtained from(1R,3R)-3-(2′-hydroxyethyl) cyclopentanol synthesized by the methoddescribed in J. Am. Chem. Soc., 99(5) 1625 (1977).

The TBS derivative (9.8 g, 40 mmol) obtained in the above (1) wasdissolved in toluene (150 mL), and to the solution was added 40% toluenesolution (35 mL, 80 mmol) containing benzoic acid (9.8 g, 80 mmol),triphenylphosphine (21 g, 80 mmol) and diethyl azodicarboxylate underice-cooling. The solution was stirred for 1 hour under ice-cooling, andwater was added thereto. The solution was stirred at room temperaturefor 30 minutes, and the resulting solid was filtered off, and thefiltrate was washed with saturated brine. The organic layer was driedover anhydrous magnesium sulfate, filtered, and concentrated. Theresulting residue was purified by a column chromatography on silica gelto obtain the above benzoyl derivative (9.8 g) as a colorless oil.

The benzoyl derivative (4.5 g, 12.9 mmol) obtained in the above (2) wasdissolved in methanol (20 mL), and then 0.05M methanol solution (150 mL)containing sodium hydroxide was added thereto under ice-cooling. Thesolution was stirred at room temperature for 12 hours. The resultingreaction solution was diluted with t-butyl methyl ether, and the organiclayer was washed successively with water and saturated brine, dried overanhydrous magnesium sulfate, filtered, and concentrated. The resultingresidue was purified by a column chromatography on silica gel to obtainthe above alcohol derivative (2.6 g) as a colorless oil.

The alcohol derivative (566 mg, 2.31 mmol) obtained in the above (3) wasdissolved in chloroform (10 mL), and to the solution were addedtriethylamine (414 μL, 2.97 mmol) and methanesulfonylchloride (231 μL,2.97 mmol) under ice-cooling. The mixture was stirred for 1 hour. Afteraqueous sodium hydrogencarbonate was added to the reaction solution, itwas extracted with chloroform. The organic layer was washed withsaturated brine, dried over anhydrous magnesium sulfate, filtered, andconcentrated to obtain the objective derivative [A-4] (746 mg) as a paleyellow oil.

Reference Example 5

Synthesis of the Compound of the Following Formula [A-5]:

The above diol derivative was obtained from norcamphor according to themethod described in J. Am. Chem. Soc., 99(5)

The above benzoyl compound was obtained from the diol derivativeobtained in the above (1) according to a method similar to theprocedures of Reference Examples 4-(1) to 4-(2).

The benzoyl derivative (4.5 g, 12.9 mmol) obtained in the above (2) wasdissolved in chloroform (80 mL), and hydrochloric acid/methanol (20 mL)was added thereto under ice-cooling. The resulting reaction solution wasstirred for 15 minutes under ice-cooling, and chloroform was addedthereto. The organic layer was washed successively with water, saturatedaqueous sodium hydrogencarbonate and saturated brine. Then, the organiclayer was dried over anhydrous magnesium sulfate, filtered, andconcentrated. The resulting residue was purified by a columnchromatography on silica gel to obtain the above alcohol derivative (2.7g) as a colorless oil.

The objective compound [A-5] (258 mg) was obtained as a pale yellow oilfrom the alcohol derivative (194 mg, 826 μmol) obtained according to theprocedure of Reference Example 4-(4).

Reference Example 6

Synthesis of the Compound of the Following Formula [A-6]:

According to a method similar to the procedures as Reference Examples4-(3) to 4-(4), the objective compound [A-6] was obtained from thebenzoyl derivative obtained in Reference Example 5-(2).

Reference Example 7

Synthesis of the Compound of the Following Formula [A-7]:

The TBS-derivative (4 g, 16 mmol) obtained in Reference Example 4-(1)was dissolved in chloroform (80 mL), and to the solution were addedtriethylamine (3.4 mL, 21 mmol), 4-dimethylaminopyridine (600 mg, 4.3mmol), and benzoyl chloride (2.2 mL, 17 mmol). The mixture was stirredat room temperature for 3 hours. Aqueous sodium hydrogencarbonatesolution was added to the resulting reaction solution, and it wasextracted with chloroform. The organic layer was washed with saturatedbrine, dried over anhydrous magnesium sulfate, filtered, and thefiltrate was concentrated. The resulting residue was purified by acolumn chromatography on silica gel to obtain the above benzoylderivative (5.6 g) as a colorless oil.

According to a method similar to the procedures of Reference Examples5-(3) to 5-(4), the objective compound [A-7](670 mg) was obtained as acolorless oil from the benzoyl derivative (583 mg, 1.68 mmol) obtainedin the above (1)

Reference Example 8

Synthesis of the Compound of the Following Formula [A-8]:

According to a method similar to the procedure of Reference Example1-(1), the above TBDPS-derivative (88.2 g) was obtained as a colorlessoil from (S)-hexane-1,5-diol (29.9 g, 253 mmol) synthesized by referringto the method described in J. Chem. Soc. Perkin Trans. I, 20 2467 (1996)and t-butyldiphenylsilyl chloride.

According to a method similar to the procedure of Reference Example4-(4), the objective compound [A-8] (652 mg) was obtained as a colorlessoil from the TBDPS-derivative (535 mg, 1.5 mmol) prepared in the above(1)

Reference Example 9

Synthesis of the Compound of the Following Formula [A-9]:

According to a method similar to the method as Reference Example 8, theobjective compound [A-9] was obtained from (R)-hexane-1,5-diol.

Reference Example 10

Synthesis of the Compound of the Following Formula [A-10]:

According to a method similar to the procedure of Reference Example7-(1), the above benzoyl compound (2.6 g) was obtained as a colorlessoil from TBDPS-derivative (2 g, 5.6 mmol) obtained in Reference Example8-(1)

The benzoyl derivative (2.5 g, 5.4 mmol) obtained in the above (1) wasdissolved in tetrahydrofuran (16 mL), and to this solution was added 1 Mtetrahydrofuran solution (16 mL) containing tetrabutylammonium fluoride.The solution was stirred at room temperature for 2 hours. The resultingreaction solution was diluted with diethyl ether (100 mL), and washedsuccessively with 0.1M phosphate buffer (pH 6.8) and saturated brine.The organic layer was dried over anhydrous magnesium sulfate, filtered,and the filtrate was concentrated. The resulting residue was purified bya column chromatography on silica gel to obtain the above alcoholderivative (1.2 g) as a colorless oil.

According to a method similar to the procedure of Reference Example4-(4), the objective compound [A-10] was obtained as a colorless oilfrom the alcohol derivative (378 mg, 1.70 mmol) prepared in the above(2). The product was used without separation and purification.

Reference Example 11

Synthesis of the Compound of the Following Formula [A-11]:

According to a method similar to the procedures of Reference Examples8-(1) and 10, the objective compound [A-11] was obtained from(R)-hexane-1,5-diol synthesized by referring to the method described inJ. Chem. Soc. Perkin Trans. I, 20 2467 (1996).

Reference Example 12

Synthesis of the Compound of the Following Formula [A-12]:

In the above formula, the stereo chemistry of the position with theasterisk * is of cis configuration.

Cis-2,5-di(ethoxycarbonyl)pyrrolidine (10.5 g, 49.1 mmol) synthesized byreferring to the method described in J. Org. Chem., 26(5)1500(1961) wasdissolved in pyridine (30 mL), and to the solution was added allylchloroformate (8.9 g, 73.6 mmol) under ice-cooling. The solution wasstirred for 30 minutes, and aqueous sodium hydrogencarbonate was addedto the resulting reaction solution. The reaction solution was extractedwith diethylether. The organic layer was washed with saturated brine,dried over anhydrous magnesium sulfate, filtered, and concentrated. Theresulting residue was purified by a column chromatography on silica gelto obtain the above protected derivative with Alloc (10.6 g) as acolorless oil.

The above protected derivative with Alloc (10.6 g, 35.4 mmol) obtainedin the above (1) was dissolved in tetrahydrofuran (170 mL), and thenlithium tetrahydroborate (3.9 g, 177 mmol) was added thereto. Themixture was stirred at room temperature for 2 hours. Methanol wasgradually added dropwise to the resulting reaction solution, and thereaction solution was diluted with aqueous sodium hydrogencarbonatesolution. This solution was extracted with ethyl acetate, and theorganic layer was washed with saturated brine, dried over anhydrousmagnesium sulfate, and filtered. The filtrate was and concentrated, andthe resulting residue was purified by a column chromatography on silicagel to obtain the above diol derivative (5.5 g) as a colorless oil.

The diol derivative (5.5 g, 25.5 mmol) obtained in the above (2) wasdissolved in chloroform (250 mL), and to the solution were addedtriethylamine (4.1 mL, 30 mmol), t-butyldimethylsilyl chloride (4.0 g,25.5 mmol), and 4-dimethylaminopyridine (940 mg, 7.7 mmol). The mixturewas stirred at room temperature for 2 hours. After aqueous sodiumhydrogencarbonate solution was added to the resulting reaction solution,it was extracted with chloroform. The organic layer was washed withsaturated brine, dried over anhydrous magnesium sulfate, and filtered.The filtrate was concentrated, and the resulting residue was purified bya column chromatography on silica gel to obtain the above racemicTBS-derivative (3.5 g) as a colorless oil.

According to a method similar to the procedure of Reference Example4-(4), the objective compound (A-12] (4.6 g) was obtained as a colorlessoil from the compound (3.5 g, 11.5 mmol) obtained in the above (3)

Reference Example 13

Synthesis of the Compound of the Following Formula [A-13]:

According to a method similar to the procedure of Reference Example12-(3), the above TBS-derivative (995 mg) was obtained as a colorlessoil from cis-4-hydroxymethylcyclohexanol (601 mg, 4.62 mmol) prepared byreference to the method described in J. Org. Chem., 35(7) 2368 (1970)

The TBS-derivative (489 mg, 2.00 mmol) obtained in the above (1) andtriethylamine (1.11 mL, 8.00 mmol) were dissolved in dimethyl sulfoxide(5 mL), and then sulfur trioxide-pyridine complex (637 mg, 4.00 mmol)was added thereto in a water-bath. The resulting reaction solution wasstirred at room temperature for 10 minutes, diluted with ethyl acetate,and washed successively with water (twice) and saturated brine. Theorganic layer was dried over anhydrous magnesium sulfate, filtered, andconcentrated in vacuo to obtain the above ketone derivative (444 mg) asa colorless oil.

The ketone derivative (121 mg, 160 μmol) obtained in the above (2) wasdissolved in tetrahydrofuran (3 mL), and to the solution was addeddropwise 1M tetrahydrofuran solution (750 μL, 750 μmol) containinglithium tri-t-buthoxy-aluminium hydride at −65° C. The resultingreaction solution was warmed up to 0° C., and saturated aqueous Rochellesalt and ethyl acetate were added thereto. The mixture was stirred atroom temperature for 1 hour. This reaction solution was extracted withethyl acetate, and the extract was washed successively with water andsaturated brine, dried over anhydrous magnesium sulfate, filtered, andconcentrated in vacuo to obtain the above trans-alcohol derivative (122mg) as a pale yellow oil.

According to a method similar to the procedure of Reference Example4-(4), the objective compound [A-13] (659 mg) was obtained as acolorless oil from the trans-alcohol derivative (518 mg, 2.12 mmol)obtained in the above (3).

Reference Example 14

Synthesis of the Compound of the Following Formula [A-14]:

To a stirred solution of (R)-(−)-ribose (5.00 g, 33.3 mmol) inN,N-dimethylformamide (10 mL) were added imidazole (4.50 g, 66.6 mmol)and t-butyldiphenylsilyl chloride (9.07 mL, 34.8 mmol) at 0° C. Thereaction solution was stirred at room temperature overnight. 1N aqueouspotassium hydrogensulfate was added to the resulting reaction solution,and the solution was stirred at room temperature for 30 minutes, andthen extracted with ethyl acetate. The organic layer was washed withsaturated brine, dried over anhydrous magnesium sulfate, filtered, andthe filtrate was concentrated. Pyridine (30 mL) and acetic anhydide (10mL) were added to the resulting residue, and the mixture was stirred atroom temperature for 2 hours. To this reaction solution was added 1Naqueous potassium hydrogensulfate, and the reaction solution wasextracted with ethyl acetate. The organic layer was washed withsaturated brine, dried over anhydrous magnesium sulfate, filtered, andthe filtrate was concentrated. The resulting residue was purified by acolumn chromatography on silica gel to obtain the above protectedderivative with TBDPS (12.3 g) as a pale yellow solid.

The protected derivative with TBDPS (11 g, 21.4 mmol) obtained in theabove (1) was dissolved in methylene chloride (60 mL), and the reactionsystem was substituted with carbon monooxide. To this solution wereadded diethylmethylsilane (22 mL, 215 mmol) and dicobalt octacarbonyl(1.0 g, 2.92 mmol), and the mixture was stirred at room temperatureovernight, after which time water was added thereto. The reactionsolution was extracted with ethyl acetate, and the organic layer waswashed with saturated brine, dried over anhydrous sodium sulfate,filtered, and concentrated in vacuo. The resulting residue was purifiedby a column chromatography on silica gel to obtain the above alcoholderivative (5.37 g) as a pale yellow solid.

To a stirred solution of the alcohol derivative (1.00 g, 2.05 mmol)obtained in the above (2) in methylene chloride (10 mL) were addedtriethylamine (860 μL, 6.15 mmol), 4,4′-dimethoxytrityl (692 mg, 780μmol) and 4-dimethylaminopyridine (251 mg, 2.05 mmol) at 0° C. Thereaction solution was stirred at room temperature for 2 hours. Water wasadded to the resulting reaction solution, and the solution was stirredat room temperature for 30 minutes, and then extracted with ethylacetate. The organic layer was washed with saturated brine, dried overanhydrous sodium sulfate, filtered, and the filtrate was concentrated.The resulting residue was purified by a column chromatography on silicagel to obtain the above tritylated derivative (765 mg) as a pale yellowsolid.

According to a method similar to the procedure of Reference Example4-(3), the above diol derivative (511 mg) was obtained as a pale yellowsolid from the tritylated derivative (711 mg, 2.05 mmol) obtained in theabove (3)

To a stirred tetrahydrofuran solution (10 mL) containing the diolderivative (511 mg, 720 μmol) obtained in the above (4) was added 60%sodium hydride dispersion in oil (116 mg, 2.90 mmol) at 0° C., and themixture was stirred at room temperature for 30 minutes. After additionof carbon disulfide (230 μL, 3.02 mmol), the reaction solution wasstirred at room temperature for 5 minutes, and methyl iodide (170 μL,2.73 mmol) was added thereto. The mixture was stirred at roomtemperature for 1 hour, and 1N aqueous potassium hydrogensulfate wasadded. The reaction solution was extracted with ethyl acetate. Theorganic layer was washed with saturated brine, dried over anhydroussodium sulfate, filtered, and the filtrate was concentrated. Theresulting residue was purified by a column chromatography on silica gelto obtain the above dithiocarbonate derivative (585 mg) as a pale yellowsolid.

To a stirred toluene solution (10 mL) containing the dithiocarbonatederivative (585 mg, 660 μmol) obtained in the above (5) were addedtributyltin hydride (360 μL, 1.23 mmol) and 2,2′-azobisisobutyronitrile(24 mg, 140 μmol) under a nitrogen atmosphere, and the mixture wasstirred overnight under heating at reflux. Water was added to thereaction solution, and it was extracted with ethyl acetate. The organiclayer was washed with saturated brine, dried over anhydrous sodiumsulfate, filtered, and the filtrate was concentrated. The resultingresidue was purified by a column chromatography on silica gel to obtainthe above intra-olefin derivative (367 mg) as a pale yellow solid.

To methylene chloride solution, (30 mL) containing the aboveintra-olefin derivative (665 mg, 990 μmol) obtained in the above (6) wasadded gradually trichloroacetic acid (160 mg, 979 μmol). The reactionsolution was stirred at room temperature for 2 hours. Aqueous sodiumhydrogencarbonate solution was added to the resulting reaction solution,and the solution was extracted with chloroform. The organic layer waswashed with saturated brine, dried over anhydrous sodium sulfate,filtered, and the filtrate was concentrated. The resulting residue waspurified by a column chromatography on silica gel to obtain the abovealcohol derivative (213 mg) as a pale yellow solid.

The alcohol derivative (1.40 g, 3.77 mmol) obtained in the above (7) wasdissolved in tetrahydrofuran (30 mL) and methanol (30 mL), and to thesolution was added platinum oxide catalyst (700 mg) under a nitrogenatmosphere. After substitution of the reaction system with hydrogen gas,the mixture was stirred at room temperature for 15 hours. The resultingreaction solution was filtered through a Celite pad to remove thecatalyst, and the filtrate was concentrated in vacuo. The resultingresidue was purified by a column chromatography on silica gel to obtainthe above tetrahydrofuran derivative (1.28 g) as a colorless oil.

(9)

According to a method similar to the procedure of Reference Example7-(1), the above benzoyl derivative (421 mg) was obtained as a colorlessoil from the tetrahydrofuran derivative (402 mg, 1.08 mmol) obtained inthe above (8).

According to a method similar to the procedure of Reference Example10-(2), the above alcohol derivative (402 mg) was obtained as a paleyellow oil from the benzoyl derivative (421 mg, 887 μmol) obtained inthe above (9)

The alcohol derivative (402 mg) obtained in the above (10) was dissolvedin diethyl ether (5 mL), and then N,N-diisopropylethylamine (223 μL,1.28 mmol) and methanesulfonyl chloride (82 μL, 1.06 mmol) were addedthereto under ice-cooling. The mixture was stirred for 2 hours. Afterdiethyl ether was added to the resulting reaction solution, the organiclayer was washed successively with 1N hydrochloric acid, water, andsaturated brine, dried over anhydrous magnesium sulfate, and filtered.The filtrate was concentrated, and the resulting residue was dissolvedin N,N-dimethylformamide (5 mL), and then sodium azide (115 mg, 1.77mmol) was added thereto. The reaction solution was stirred at 80° C. for12 hours, and cooled down to room temperature. After addition of ethylacetate to this reaction solution, the organic layer was washedsuccessively with water and saturated brine, dried over anhydrousmagnesium sulfate, and filtered. The filtrate was concentrated, and theresulting residue was dissolved in tetrahydrofuran (5 mL) and methanol(5 mL), and 10% palladium carbon catalyst (700 mg) was added theretounder a nitrogen atmosphere. The atmosphere in the reaction system wassubstituted with hydrogen gas, and the solution was stirred at roomtemperature for 3 hours. The resulting solution was filtered through aCelite pad to remove the catalyst, and the filtrate was concentrated invacuo. The resulting residue was purified by a silica gel chromatographyto obtain the objective compound [A-14] (81 mg) as a colorless oil.

Reference Example 15

Synthesis of the Compound of the Following Formula [A-15]:

Ethyl(3R,5S)-3-(t-butyldiphenylsilyloxy)tetrahydro-5-furanylacetate(11.9 g, 29 mmol) prepared according to a method similar to the methoddescribed in Tetrahedron Lett., 26(9) 1185 (1985) was dissolved in ether(100 mL), and lithium aluminium hydride (660 mg, 1.7 mmol) was addedthereto in an ice-bath. The reaction solution was stirred at roomtemperature for 1 hour. Anhydrous sodium sulfate decahydrate (3 g) wasadded thereto in an ice-bath, and the mixture was stirred at roomtemperature for 2 hours. The reaction solution was dried over anhydrousmagnesium sulfate, and filtered through a Celite pad to remove theinsolubles. The filtrate was concentrated in vacuo to obtain the aboveprimary alcohol derivative (9.52 g) as a colorless oil.

According to a method similar to the procedure of Reference Example14-(11), the objective compound [A-15] (2.27 g) was obtained as acolorless oil from the primary alcohol derivative (2.50 g, 6.75 mmol)obtained in the above (1)

Reference Example 16

Synthesis of the Compound of the Following Formula [A-16]:

4-Acetoxypiperidine hydrochloride (1.5 g, 8.6 mmol) prepared byreferring to EP122855 and t-butyl-N-(2-oxoethyl)carbamate (1.1 g, 6.9mmol) were dissolved in methanol (20 mL). To the solution wasportionwise added sodium cyanotrihydroborate (641 mg, 10 mmol) in anice-water bath, and the mixture was stirred at room temperature for 2hours. The resulting reaction solution was concentrated in vacuo, pouredinto aqueous sodium hydrogencarbonate solution, and extracted withchloroform three times. The resulting extract was dried over anhydroussodium sulfate, and filtered. The filtrate was concentrated in vacuo andthe resulting residue was purified by a column chromatography to obtainthe above N-alkylpiperidin derivative (850 mg) as a colorless oil.

4N hydrogen chloride/1,4-dioxane solution (5 mL) was added to theN-alkylpiperidine derivative (850 mg, 3.0 mmol) obtained in the above(1) at room temperature, and the mixture was stirred at room temperaturefor 2 hours. The resulting reaction solution was concentrated in vacuoto obtain the objective compound [A-16] (666 mg) as a white solid.

Reference Example 17

Synthesis of the Compound of the Following Formula [A-17]:

To a solution of (t-butyldimethylsilyloxy)acetaldehyde (5.00 g, 28.6mmol) in chloroform (50 mL) was added the allyl carbazinate derivative(5.00 g, 43.1 mmol) prepared by referring to JP 04117361, and themixture was stirred at room temperature for 15 hours. After addition ofsaturated brine to the resulting reaction solution, the organic layerwas separated. The resulting organic layer was dried over anhydrousmagnesium sulfate, filtered, and the filtrate was concentrated. To theresulting residue were added zinc chloride (1.02 g, 75.0 mmol) andmethanol solution (500 mL) containing sodium cyanotrihydroborate (1.41g, 150 mmol), and the mixture was stirred at room temperature for 2days. After hexane and ethyl acetate were added to the resultingreaction solution, it was filtered through a Celite pad, and thefiltrate was washed with water and saturated brine. The organic layerwas dried over anhydrous magnesium sulfate, filtered, and the filtratewas concentrated. The resulting residue was purified by a chromatographyon silica gel to obtain the objective compound [A-17] (5.03 g) as acolorless oil.

Reference Example 18

Synthesis of the Compound of the Following Formula [A-18]:

According to a method similar to the procedure of Reference Example13-(2), the above aldehyde derivative (1.51 g) was obtained as acolorless oil from the de-TBDPS derivative (1.56 g, 7.0 mmol) obtainedin Reference Example 10-(2).

(2)

According to a method similar to the procedure of Reference Example 17,the objective compound [A-18] (1.33 g) was obtained as a colorless oilfrom the aldehyde derivative (1.51 g, 6.9 mmol) obtained in the above(1).

Reference Example 19

Synthesis of the Compound of the Following Formula [A-19]:

According to a method similar to the method as Reference Examples 8-(1)and 10-(1) to 10-(2), the above primary alcohol derivative was obtainedfrom (R)-hexane-1,5-diol which is a starting material of ReferenceExample 11

According to a method similar to the procedure as Reference Example 18,the objective compound [A-19] was obtained from the primary alcoholderivative obtained in the above (1)

Reference Example 20

Synthesis of the Compound of the Following Formula [A-20]:

According to a method similar to the procedure of Reference Example 17,the objective compound [A-20] (335 mg) was obtained as a colorless oilfrom 5-t-butyldiphenylsilyloxy-1-pentanal (500 mg, 1.47 mmol)synthesized by referring to the method described in J. Org. Chem.,59(2), 324 (1994) and t-butyl carbazinate (194 mg, 1.47 mmol)

Reference Example 21

Synthesis of the Compound of the Following Formula [A-21]:

According to a method similar to the procedure of Reference Example 17,the objective compound [A-21] (7.40 g) was obtained as a colorless oilfrom the ketone derivative (10.8 g, 30.4 mmol) synthesized by referringto the method described in Tetrahedron Lett., 56(8) 1065 (2000).

Reference Example 22

Synthesis of the Compound of the Following Formula [A-22]:

Racemic 3-hydroxypiperidine hydrochloride (662 mg, 4.81 mmol) wasdissolved in a mixed solution of water (2 mL) and 1,4-dioxane (4 mL),and to this solution was added 4N aqueous sodium hydroxide (3 mL). Tothis solution was added di-t-butyl dicarbonate (1.11 mL, 4.81 mmol).After the solution was stirred at room temperature for 7 hours, ethylacetate was added to the resulting reaction solution for extraction. Theorganic layer was washed successively with water and saturated brine,dried over anhydrous magnesium sulfate, filtered, and concentrated invacuo to obtain the above protected derivative with Boc (968 mg) as acolorless oil.

The resulting protected derivative with Boc (968 mg, 4.81 mmol) wasdissolved in N,N-dimethylformamide (5 mL), and then methyl iodide (449μL, 7.22 mmol) was added thereto. After addition of sodium hydride (231mg, 60% dispersion in oil, 5.77 mmol) under ice-cooling, the mixture wasstirred for 5 minutes at the same temperature. The resulting reactionsolution was warmed up to room temperature, and stirred for further 10hours. After saturated aqueous ammonium chloride solution was added tothis solution, it was extracted with a mixed solvent of hexane and ethylacetate. The organic layer was washed with water and saturated brine,dried over anhydrous magnesium sulfate, and filtered. The filtrate wasconcentrated in vacuo, and azeotropic evaporation was carried out usingtoluene. The residue was purified by a column chromatography on silicagel to obtain the above methyl ether derivative (885 mg) as a colorlessliquid.

The resulting methyl ether derivative (885 mg) was dissolved inchloroform (5 mL), and to this solution was added 4N hydrogenchloride/1,4-dioxane solution (5 mL). The solution was stirred at roomtemperature for 2 hours, and the resulting reaction solution wasconcentrated in vacuo to obtain the racemic objective compound [A-22](596 mg) as a white solid.

Reference Example 23

Synthesis of the Compound of the Following Formula [A-23]:

According to a method similar to the procedure of Reference Example 22,the objective compound [A-23] was obtained from (R)-3-hydroxypiperidinehydrochloride.

Reference Example 24

Synthesis of the Compound of the Following Formula [A-24]:

According to a method similar to the procedure as Reference Example 22,the objective compound [A-24] was obtained from (S)-3-hydroxypiperidinesynthesized according to the method described in Tetrahedron Lett.,51(21) 5935 (1995).

Reference Example 25

Synthesis of the Compound of the Following Formula [A-25]:

According to a method similar to the procedure of Reference Example 22,the racemic objective compound [A-25] (352 mg) was obtained as a whitesolid from racemic 3-hydroxymethylpiperidine (569 mg, 4.94 mmol).

Reference Example 26

Synthesis of the Compound of the Following Formula [A-26]:

According to a method similar to the procedure of Reference Example 22,the racemic objective compound [A-26] (899 mg) was obtained as a whitesolid from racemic 2-hydroxymethylpiperidine (857 mg, 7.44 mmol).

Reference Example 27

Synthesis of the Compound of the Following Formula [A-27]:

According to a method similar to the procedure as Reference Example 22,the objective compound [A-27] was obtained from(R)-2-hydroxymethylpiperidine synthesized according to the methoddescribed in Heterocycles, 41(9) 1931 (1995).

Reference Example 28

Synthesis of the Compound of the Following Formula [A-28]:

According to a method similar to the procedure as Reference Example 22,the objective compound [A-28] was obtained from(S)-2-hydroxymethylpiperidine synthesized according to the methoddescribed in Heterocycles, 41(9) 1931 (1995),

Reference Example 29

Synthesis of the Compound of the Following Formula [A-29]:

According to a method similar to the procedure of Reference Example 22,the objective compound [A-29] (222 mg) was obtained as a milky yellowsolid from 4-hydroxypiperidine (251 mg, 2.48 mmol).

Reference Example 30

Synthesis of the Compound of the Following Formula [A-30]:

To a solution of 5-hydroxypentanal oxime (300 mg, 2.56 mmol) in methanol(10 mL) was added sodium cyanotrihydroborate (193 mg, 3.07 mmol), andthen a mixture of conc. hydrochloric acid and methanol was addeddropwise so as to adjust the pH to 3. The mixture was stirred for 30minutes. After this solution was neutralized using aqueous sodiumhydroxide, it was concentrated. The resulting residue was purified by acolumn chromatography on silica gel to obtain the above hydroxylaminederivative (299 mg) as a colorless oil.

According to a method similar to the procedure of Reference Example1-(1), the objective compound [A-30] (481 mg) was obtained as a paleyellow oil from the hydroxylamine derivative (235 mg, 1.97 mmol)obtained in the above (1).

Reference Example 31

Synthesis of the Compound of the Following Formula [A-31]:

To a solution of t-butyl carbazinate (350 mg, 2.65 mmol) in pyridine (5mL) was added 4-nitrobenzenesulfonyl chloride (590 mg, 2.65 mmol) in anice-bath, and the mixture was stirred at room temperature for 1 hour.After the resulting reaction solution was diluted with chloroform, itwas washed successively with 1N hydrochloric acid and saturated brine.The organic layer was dried over anhydrous magnesium sulfate, filtered,and concentrated in vacuo to obtain the above sulfone hydrazidederivative (910 mg) as a white solid.

According to a method similar to the procedure of Reference Example 17,the above amine derivative (599 mg) was obtained from(t-butyldimethylsilyloxy)acetaldehyde (500 μL) andN-methyl-2-aminoethanol (200 μL)

According to a method similar to the procedure of Reference Example4-(2), the above N-alkylsulfone hydrazide derivative (1.35 g) wasobtained as a pale yellow solid from the sulfone hydrazide derivative(815 mg, 2.57 mmol) obtained in the above (1) and the amine derivative(599 mg, 2.57 mmol) obtained in the above (2)

According to a method similar to the method described in Journal ofSynthetic Organic Chemistry, Japan 59(8) 779 (2001), deprotection of the4-nitrobenzenesulfonyl group was carried out to obtain the objectivecompound [A-31] (576 mg) as a colorless oil from the N-alkylsulfonehydrazide derivative (1.35 g) obtained in the above (3)

Reference Example 32

Synthesis of the Compound of the Following Formula [A-32]:

In the structure, the stereo chemistry of the position with the symbol *is of cis-configuration.

To a solution of racemic 2-azabicyclo[2,2,1]hept-5-ene-3-one (1.12 g,10.2 mmol) in ethanol (20 mL) was added 10% palladium carbon (250 mg),and atmosphere in the reaction system was substituted with hydrogen gas.The mixture was stirred at room temperature for 3 hours under normalpressure. The resulting reaction solution was filtered through a Celitepad, and the filtrate was concentrated to obtain the above racemicreduced derivative (1.14 g) as a colorless oil.

The racemic reduced derivative (1.85 g, 16.6 mmol) obtained in the above(1) was dissolved in methylene chloride (30 mL), and then di-t-butyldicarbonate (3.63 g, 16.6 mmol), triethylamine (6.00 mL, 43.1 mmol) and4-dimethylaminopyridine (3.23 g, 26.4 mmol) were added to the solutionat 0° C. with stirring, and the mixture was stirred overnight at roomtemperature. 1N potassium hydrogensulfate solution was added to theresulting reaction solution, and it was extracted with ethyl acetate.The organic layer was washed with saturated brine, dried over anhydroussodium sulfate, and filtered. The filtrate was concentrated in vacuo toobtain the above racemic protected derivative with Boc (2.24 g) as acolorless solid.

The racemic protected derivative with Boc (1.00 g, 4.73 mmol) obtainedin the above (2) was dissolved in methanol (20 mL), and to this solutionwas added potassium carbonate (654 mg, 4.73 mmol) at 0° C. withstirring. The solution was stirred at room temperature for 1 hour. Waterwas added the resulting reaction solution, and it was extracted withethyl acetate. The organic layer was washed with saturated brine, driedover anhydrous sodium sulfate, filtered, and the filtrate wasconcentrated in vacuo to obtain the above racemic ester derivative (1.00g) as a colorless solid.

According to a method similar to the procedure of Reference Example12-(2), the racemic alcohol derivative (884 mg) was obtained as acolorless solid from the racemic ester derivative (1.00 g, 4.11 mmol)prepared in the above (3)

According to a method similar to the procedure of Reference Example16-(2), the racemic objective derivative [A-32] (151 mg) was obtained asa yellow oil from the racemic alcohol derivative (215 mg, 1.00 mmol)obtained in the above (4).

Reference Example 33

Synthesis of the Compound of the Following Formula [A-33]:

(2R,4R)-1-(buthoxycarbonyl)-4-hydroxy-2-methylpyrrolidine (861 mg)prepared by referring to the method described in Tetrahedron Lett.,54,10029 (1988) was dissolved in 4N hydrogen chloride/1,4-dioxanesolution (3 mL), and the solution was stirred at room temperature for 19hours. The reaction solution was concentrated, filtered, washed withdiethyl ether, and dried to obtain a white solid (338 mg). 0.5M methanolsolution (5.4 mL) containing sodium methoxide was added to this whitesolid, and the mixture was stirred for 1 hour. The resulting reactionsolution was filtered, and the mother liquor was concentrated to give aresidue, to which was added chloroform (2 mL). The mixture was stirredfor 30 minutes, and the resulting suspension was filtered. The motherliquor was concentrated, and distilled to obtain the objective compound[A-33] (205 mg) as a colorless clear oil.

Reference Example 34

Synthesis of the Compound of the Following Formula [A-34]:

According to a method similar to the procedure of Reference Example31-(1), the above sulfone hydrazide derivative (3.22 g) was obtained asa white solid from the allyl carbazinate derivative (2.00 g, 17.2 mmol)synthesized by referring to the method described in JP 04117361.

According to a method similar to the procedure of Reference Example4-(1), the above N-alkylsulfone hydrazide derivative (1.08 g) wasobtained as a colorless oil from(S)-1-(t-butyldimethylsiloxy)-2-propanol (678 mg, 3.56 mmol) synthesizedby referring to the method described in J. Org. Chem., 53(10) 2300(1988).

Deprotection of the 4-nitrobenzenesulfonyl group of the N-alkylsulfonehydrazide derivative (1.08 g) obtained in the above (2) was carried outaccording to a method similar to the method described in Journal ofSynthetic Organic Chemistry, Japan 59(8) 779 (2001), to obtain theobjective compound [A-34] (304 mg) as a colorless oil.

INDUSTRIAL APPLICABILITY

As described above, the compounds of the present invention have strongCdk inhibitory activity. Since the compounds of the present inventionalso show strong inhibitory activity of BrdU uptake, they have clearlyinhibitory activity of cell growth. Therefore, the compounds of thepresent invention are useful as an anti-cancer agent (agent for thetreatment of cancers). That is, it is considered that anti-cancer agentscontaining a new quinoxalinone derivative or a salt or ester thereof ofthe present invention are useful for the treatment of cancer patients.

1. A quinoxalinone derivative of the formula (I):

or a pharmaceutically acceptable salt or ester thereof, wherein; X isNH, S, O or CH₂; Y is O or NR′, wherein R′ is hydrogen or lower alkyl;the partial structure

is selected from the following formula:

wherein B₁, B₂, . . . , B_(n-1) and B_(n), and B′₁, B′₂, . . . ,B′_(n-1) and B′_(n) (in which n is 4, 5 or 6) are each defined asfollows: B₁, B₂, . . . , B_(n-1) and B_(n) are each independently C, CH,CRo, N or O (wherein when B₁, B₂, . . . , B_(n-1) and B_(n) are eachindependently C, then B′₁, B′₂, . . . , B′_(n-1) and B′_(n) are oxo,respectively; when B₁, B₂, . . . B_(n-1) and B_(n) are eachindependently O, then B′₁, B′₂, . . . , B′_(n-1) and B′_(n) are eachtaken together with B₁, B₂, . . . , B_(n-1) and B_(n), respectively, toform O, with the proviso that two or more members of B₁, B₂, . . . ,B_(n-1) and B_(n), at the same time, are not taken together with B′₁,B′₂, . . . , B′_(n-1) and B′₁, respectively, to form 0; and R₀ is loweralkyl), and B′₁, B′₂, . . . , B′_(n-1) and B′_(n) are each independentlyhydrogen, halogen, hydroxy, oxo, lower alkoxy, amino, lower alkylamino,di-lower alkylamino, lower alkyl or lower alkenyl (wherein said loweralkyl and said lower alkenyl may be substituted with one or more, sameor different substituents selected from the group consisting of hydroxy,lower alkoxy, amino and lower alkylamino, and among B′₁, B′₂, . . . ,B′_(n-1) and B′_(n), B′_(i) and B40 _(i+2) (in which i is 1, 2 or 3)taken together with B_(i), B_(i+1) and B_(i+2), or B′_(i) and B′_(i+3)(in which i is 1 or 2) taken together with B_(i), B_(i+1), B_(i+2) andB_(i+3), may form a C₅-C₆ cycloalkyl or an aliphatic heterocyclic groupselected from <substituent group β₁>, and said cycloalkyl and saidaliphatic heterocyclic group may be substituted with one or more, sameor different substituents selected from lower alkyl and <substituentgroup α>); R is hydrogen, lower alkyl, lower alkenyl, amino in which thenitrogen atom is di-substituted with R_(a) and R_(b), amino-lower alkylin which the nitrogen atom is di-substituted with R_(a) and R_(b), or L,wherein R_(a) and R_(b) are each independently hydrogen, lower alkyl,lower alkoxyalkyl or halogenated lower alkyl, and L is L₁-L₂-L₃ (whereinL₁ is a single bond, —(CH₂)_(k1)—, —(CH₂)_(k1)—O— or —(CH₂)_(k1)—NH— (inwhich k1 is an integer of 1 to 3); L₂ is a single bond or —(CH₂)_(k2)—(in which k2 is an integer of 1 to 3); and L₃ is lower alkyl, loweralkoxy, C₃-C₆ cycloalkyl, phenyl, pyridyl, pyrrolidinyl or piperidinyl,said lower alkyl, lower alkoxy, C₃-C₆ cycloalkyl, phenyl, pyridyl,pyrrolidinyl or piperidinyl being optionally substituted with one ormore fluorine atoms); or a substituent selected from <substituent groupα>, which may be substituted with one or more, same or differentsubstituents selected from <substituent group γ>, or lower alkylsubstituted with said substituent; or a cyclic group selected from<substituent group β₂>, which may be substituted with one or more, sameor different substituents selected from a lower alkyl, <substituentgroup α>and <substituent group γ>and also may be substituted with J(wherein J is J₁-J₂-J₃; J₁ is a single bond, —C(═O)—, —O—, —NH—, —NHCO—,—(CH₂)_(k3)— or —(CH₂)_(k3)—O— (in which k3 is an integer of 1 to 3); J₂is a single bond or —(CH₂)_(k4)— (in which k4 is an integer of 1 to 3);and J₃ is lower alkyl, lower alkoxy, —CONR_(a)R_(b) (wherein R_(a) andR_(b) each have the same meaning as defined above), phenyl, pyridyl,pyrrolidinyl or piperidinyl, said lower alkyl, lower alkoxy, phenyl,pyridyl, pyrrolidinyl or piperidinyl being optionally substituted withone or more fluorine atoms), or lower alkyl substituted with said cyclicgroup, and in the above, <substituent group α>, <substituent group β₁>,<substituent group β2>and <substituent group γ>each have the meaningsshown below: <substituent group α> hydroxy, hydroxy-lower alkyl, cyano,halogen, carboxyl, lower alkanoyl, lower alkoxycarbonyl, lower alkoxy,lower alkoxyalkyl, amino, lower alkylamino, lower alkylsulfonyl,halogenated lower alkyl, halogenated lower alkoxy, halogenated loweralkylamino, nitro and lower alkanoylamino, <substituent group β₁>

<substituent group β₂>

substituent group γ> C₃-C₆ cycloalkyl, lower alkyl substituted withC₃-C₆ cycloalkyl, phenyl, lower alkyl substituted with phenyl, pyridyl,pyrrolidinyl and piperidinyl, said C₃-C₆ cycloalkyl, phenyl, pyridyl,pyrrolidinyl and piperidinyl being optionally substituted with one ormore fluorine atoms.
 2. The compound according to claim 1 or apharmaceutically acceptable salt or ester thereof, wherein; X is NH orS; and Y is O.
 3. The compound according to claim 2 or apharmaceutically acceptable salt or ester thereof, wherein; the partialstructure

is the formula:


4. The compound according to claim 3 or a pharmaceutically acceptablesalt or ester thereof, wherein; B₁, B₂, B₃, B₄ and B₅ are eachindependently CH; or B₁, B₂, B₄ and B₅ are each independently CH, and B₃is N or O.
 5. The compound according to claim 4 or a pharmaceuticallyacceptable salt or ester thereof, wherein; the <substituent group α>isselected from hydroxy, hydroxy-lower alkyl, halogen, loweralkoxycarbonyl, lower alkoxy, lower alkoxyalkyl, lower alkylamino,methyl substituted with one to three fluorine atoms, methoxy substitutedwith one to three fluorine atoms and lower alkylamino substituted withone to three fluorine atoms; and the <substituent group β₁>is


6. The compound according to claim 5 or a pharmaceutically acceptablesalt or ester thereof, wherein; B₁, B₂, B₄ and B₅ are each independentlyCH, B₃ is N, and all of B′₁, B′₂, B′₃, B′₄ and B′₅ are hydrogen; or oneof B′₁, B′₂, B′₃, B′₄ and B′₅ is lower alkyl or lower alkenyl, and allthe others are hydrogen; or at least two of B′₁, B′₂, B′₃, B′₄ and B′₅are each independently lower alkyl or lower alkenyl, and all the othersare hydrogen; or among B′₁, B′₂, B′₃, B′₄ and B′₅, B′_(i) and B′_(i+2)(in which i is 1, 2 or 3) taken together with B_(i), B_(i+1) and B_(i+2)form an aliphatic heterocycle selected from <substituent group β₁>(wherein said aliphatic heterocycle may be substituted with one or more,same or different substituents selected from lower alkyl and<substituent group a>), and the others are hydrogen, lower alkyl orlower alkenyl.
 7. The compound according to claim 6 or apharmaceutically acceptable salt or ester thereof, wherein; X is NH; B₁,B₂, B₄ and Bs are each independently CH, and B₃ is N; among B′₁, B′₂,B′₃, B′₄ and B′₅, B′_(i) and B′_(i+2) (in which i is 1) taken togetherwith B_(i), B_(i+1) and B_(i+2) form an aliphatic heterocycle selectedfrom <substituent group β₁> (wherein said aliphatic heterocycle may besubstituted with lower alkyl), and the others are hydrogen.
 8. Thecompound according to claim 2 or a pharmaceutically acceptable salt orester thereof, wherein; the partial structure

is the formula:

wherein B₁, B₂, B₃, Bs and B₆ are each independently CH, and B₄ is N;among B′₁, B′₂, B′₃, B′₄, B′₅ and B′₆, B′_(i) and B′_(i+3) (in which iis 1 or 2) taken together with B_(i), B_(i+1), B_(i+2) and B_(i+3) form

and all the others are hydrogen.
 9. The compound according to claim 6 ora pharmaceutically acceptable salt or ester thereof, wherein; the Rbinds to quinoxalinone as described in the following formula:


10. The compound according to claim 9 or a pharmaceutically acceptablesalt or ester thereof, wherein; R is hydrogen, amino-lower alkyl inwhich the nitrogen atom is di-substituted with R_(a) and R_(b), or L,wherein R_(a) and R_(b) are each independently lower alkyl, and L isL₁-L₂-L₃ (wherein L₁ is a single bond, —(CH₂)_(k1)—, —(CH₂)_(k1)—O— or—(CH₂)_(k1)—NH— (in which k1 is an integer of 1 or 2); L₂ is a singlebond or —(CH₂)_(k2)— (in which k2 is an integer of 1 or 2); and L₃ islower alkoxy or C₃-C₆ cycloalkyl); or a cyclic group selected from<substituent group β₂>, which may be substituted with one or more, sameor different substituents selected from lower alkyl and <substituentgroup α>, or lower alkyl substituted with said cyclic group, wherein the<substituent group β₂> is selected from

and the <substituent group α> is selected from halogen, lower alkoxy,lower alkoxyalkyl, methyl substituted with one to three fluorine atoms,and methoxy substituted with one to three fluorine atoms; or lower alkylsubstituted with a substituent selected from the group consisting oflower alkylamino and lower alkylamino substituted with one to threefluorine atoms.
 11. The compound according to claim 2 or apharmaceutically acceptable salt or ester thereof, wherein; the partialstructure

is selected from the group consisting of

wherein R″ is hydrogen or methyl; and R is selected from the groupconsisting of


12. The compound according to claim 11 or a pharmaceutically acceptablesalt or ester thereof, wherein; X is NH; and the partial structure

is the formula:

wherein R″ is methyl.
 13. The compound according to claim 1 or apharmaceutically acceptable salt or ester thereof, wherein; thequinoxalinone derivative is


14. A pharmaceutical composition comprising one or more kinds of thequinoxalinone derivative according to claim 1 as an active ingredient,together with a pharmaceutically acceptable carrier or diluent.
 15. ACdk inhibitor comprising one or more kinds of the quinoxalinonederivative according to claim 1 as an active ingredient, together with apharmaceutically acceptable carrier or diluent.
 16. An anti-cancer agentcomprising one or more kinds of the quinoxalinone derivative accordingto claim 1 as an active ingredient, together with a pharmaceuticallyacceptable carrier or diluent.
 17. The compound according to claim 7 ora pharmaceutically acceptable salt or ester thereof, wherein; the Rbinds to quinoxalinone as described in the following formula:


18. The compound according to claim 8 or a pharmaceutically acceptablesalt or ester thereof, wherein; the R binds to quinoxalinone asdescribed in the following formula: